Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

l-Arabinose improves hypercholesterolemia via regulating bile acid metabolism in high-fat-high-sucrose diet-fed mice

l-Arabinose improves hypercholesterolemia via regulating bile acid metabolism in... Background: Hypercholesterolemia is closely associated with an increased risk of cardiovascular diseases. l -Arab- inose exhibited hypocholesterolemia properties, but underlying mechanisms have not been sufficiently investigated. This study aimed to elucidate the mechanisms of l -arabinose on hypocholesterolemia involving the enterohepatic circulation of bile acids. Methods: Thirty six-week-old male mice were randomly divided into three groups: the control group and the high- fat-high-sucrose diet (HFHSD)-fed group were gavaged with distilled water, and the l -arabinose-treated group were fed HFHSD and received 400 mg/kg/day l -arabinose for 12 weeks. Serum and liver biochemical parameters, serum and fecal bile acid, cholesterol and bile acid metabolism-related gene and protein expressions in the liver and small intestine were analyzed. Results: l -Arabinose supplementation significantly reduced body weight gain, lowered circulating low-density lipo - protein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C) levels, and efficiently allevi- ated hepatic inflammation and lipid accumulations in HFHSD-fed mice. l -Arabinose inhibited cholesterol synthesis via downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Additionally, l -arabinose might facilitate reverse cholesterol transport, evidenced by the increased mRNA expressions of low-density lipoprotein receptor (LDL-R) and scavenger receptor class B type 1 (SR-B1). Furthermore, l -arabinose modulated ileal reabsorption of bile acids mainly through downregulation of ileal bile acid-binding protein (I-BABP) and apical sodium-dependent bile acid transporter (ASBT ), resulting in the promotion of hepatic synthesis of bile acids via upregulation of cholesterol- 7α-hydroxylase (CYP7A1). Conclusions: l -Arabinose supplementation exhibits hypocholesterolemic effects in HFHSD-fed mice primarily due to regulation of bile acid metabolism-related pathways. Keywords: l -Arabinose, Cholesterol metabolism, Bile acid, Hypercholesterolemia Introduction Cardiovascular diseases (CVD) are the leading deter- minant of death worldwide, and abnormal cholesterol metabolism is strongly associated with an elevated risk *Correspondence: liyan0520@jiangnan.edu.cn; wangli@jiangnan.edu.cn of CVD [1]. Along with unhealthy dietary habits and life- Yu Wang, Jiajia Zhao and Qiang Li have contributed equally to this work styles, such as excessive intake of high-fat-high-sucrose State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China diet (HFHSD), the prevalence of hypercholesterolemia Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Nutrition & Metabolism (2022) 19:30 Page 2 of 11 increases year by year [2]. Epidemiological evidence has [17]. Bile acid synthesis includes the classical path- demonstrated that ascending levels of total cholesterol way and alternative pathway mediated by cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase contribute to the development of CVD, while the high- (CYP27A1) respectively, and is modulated by nuclear density lipoprotein cholesterol (HDL-C) is related to receptor farnesoid X receptor (FXR)-mediated negative decreased risk for CVD events [3, 4]. Thus, amelioration feedback regulation [18, 19]. Moreover, the reabsorp- or reversion of the progression of hypercholesterolemia tion of intestinal bile acids, which enables bile acids to might be the target of CVD prevention. However, pro- return to the liver and maximizes the use of it through longed administration of drugs for hypercholesterolemia enterohepatic circulation, also has a vital influence on may induce undesirable side effects [3]. Therefore, dietary cholesterol homeostasis [20, 21]. Previous studies have intake of cholesterol-lowering natural products has been clearly revealed that the hypocholesterolemic action of considered as potential candidates suitable for patients functional foods supplement is closely related to enter- with low or moderate hypercholesterolemia. ohepatic circulation of bile acids [22, 23]. Therefore, it l-Arabinose, an aldopentose in plants, usually is necessary to consider the regulatory effect of l -ara- extracted from corn cobs, beet pulp, or wheat bran, binose on cholesterol metabolism from the perspective has been proved to possess benefits in alleviating lipid of bile acid metabolism. metabolic disorder, improving insulin resistance, and Although previous studies have shown the hypocho- anti-inflammation [5, 6]. Previous studies have demon- lesterolemia properties of l -arabinose, how l -arabinose strated that l-arabinose effectively alleviates hyperlipi - improved cholesterol homeostasis via the modulation demia caused by the high consumption of dietary fat and of bile acid metabolism needs further research. In the sucrose [7]. For instance, l-arabinose treatment showed present study, hypercholesterolemic mice induced by cholesterol-lowering properties according to lowering HFHSD were applied to assess the effect and possible triglyceride (TG), TC, and LDL-C levels and increasing molecular mechanisms of cholesterol-lowering in the HDL-C levels in metabolic syndrome rats induced by a regulation of bile acid metabolism after l -arabinose high-carbohydrate, high-fat (HCHF) diet [8]. Recently, supplementation. The results showed that dietary it was reported that l-arabinose could alleviate high-fat- l -arabinose exhibited effects on alleviating HFHSD- diet-induced metabolic syndrome in mice by modulat- induced hypercholesterolemia through regulating bile ing the expression of genes governing lipid metabolism acid metabolism. and mitochondrial function, effectively restoring altered lipid profile both in the serum and liver [9]. Furthermore, the major mechanism underlying l-arabinose’s hypolipi - Methods demic effects may be attributed to inhibition of intestinal Materials and chemicals sucrase activity, thereby delaying sucrose utilization, and l-Arabinose was obtained from Sigma-Aldrich consequently reducing lipogenesis [7, 10, 11]. Although (W325512). LDL-C and HDL-C enzymatic reagent the intervention of l-arabinose exhibited cholesterol- kits were purchased from Nanjing Jiancheng Bioengi- lowering effects, the underlying mechanisms remain to neering Institute (Nanjing, China). LabAssay TG and be further investigated. LabAssay TC were obtained from WAKO ( Japan). Total Maintaining cholesterol homeostasis is crucial for bile acid assay kit was purchased from Huijia Biotech- metabolic health. Cholesterol metabolism comprises nology (Huijia Biotechnology, China). RNAiso Plus and a tightly regulated process of cholesterol biosynthesis, Prime Script RT system were purchased from Takara absorption, transport, and catabolism, which involves Biomedical Technology (Beijing, China). Primary diverse transporters, enzymes, and receptor proteins antibodies against 3-hydroxy-3-methylglutaryl-CoA [12, 13]. Both inhibition of cholesterol synthesis in reductase (HMGCR), sterol regulatory element bind- the liver and acceleration of reverse transport from ing protein-1c (SREBP-1c), and bile acid transporter peripheral tissue to liver, representing major hypocho- (ASBT) were purchased from Proteintech (IL, USA). lesterolemic mechanisms, are beneficial to lowering Antibodies against CYP7A1, hepatic nuclear factor 4α circulating cholesterol levels [14, 15]. Since choles- (HNF-4α), and Ileal-bile acid-binding protein (I-BABP) terol is the precursor to bile acid synthesis in the liver, were purchased from Santa Cruz Biotechnology (CA, no doubt regulating cholesterol homeostasis is influ - USA). Antibodies against CYP27A1 and oxysterol enced profoundly by bile acid metabolism [16]. The 7α-hydroxylase (CYP7B1) were acquired from Abcam enterohepatic circulation of bile acids contains a com- (Cambridge, UK). Antibodies against FXR, GAPDH, plex network of hepatic bile acid synthesis and excre- and HSP90 were purchased from Cell Signaling Tech- tion, intestinal reabsorption, and transport to the liver nology (MA, USA). W ang et al. Nutrition & Metabolism (2022) 19:30 Page 3 of 11 Animal qRT-PCR was performed using the ABI 7900 RT-PCR C57BL/6  J male mice (6  weeks old, 18–20  g) were pur- system (Applied Biosystem, USA) for the expression lev- chased from Shanghai SLAC Laboratory Animal Co., els of genes related to cholesterol and bile acid metabo- Ltd (Shanghai, China). All mice were kept in specific lism. The relative mRNA expression level was normalized pathogen-free conditions (24 ± 2 °C, 60% relative humid- to 18S. The sequences of qRT-PCR primers were shown ity, and 12  h light/dark cycle) and given food and water in Additional file 1: Table S1. ad  libitum. All animal protocols and procedures were performed following the approval from the Laboratory Western blot analysis Animal Ethics Committee of Jiangnan University (Uni- Western blot analysis was performed according to the versity JN. No20190315c0320630 [26]). After 1  week of method described previously [25]. Liver or ileum tissues acclimation, thirty mice were randomly divided into the were homogenized using RIPA lysis buffer (Beyotime, control group, the high-fat-high-sucrose diet-fed group Shanghai, China). After complete lysis and collection of (HFHSD group), and HFHSD fed mice receiving l-ara - the supernatant, the protein concentration was deter- binose (HFHSD + L-Ara group, Sigma-Aldrich, admin- mined using the BCA protein assay reagent (Beyotime, istrated intragastrically with 400  mg/kg/day l-arabinose Shanghai, China). 30 μg of each protein sample was sepa- for 12  weeks). The selection of dose was based on pre - rated on 10% SDS-PAGE and then transferred to polyvi- vious research [6]. The control and HFHSD groups were nylidene fluoride (PVDF) membranes. The membranes intragastrically administrated with same volume of dis- were incubated with corresponding primary antibodies tilled water per day. Mice in HFHSD and HFHSD + L-Ara overnight at 4  °C. Subsequently, membranes were incu- group received a high-fat diet (Research Diets, D12492), bated with appropriate secondary antibodies at room accompanied by a 10% glucose solution (Sigma-Aldrich) temperature for 1.5  h. The protein expression level was for 12  weeks. Urine and feces were collected and stored normalized to the HSP90 or GAPDH. The quantification at − 80 °C at the end of the experiments. The body weight of the protein band intensity was determined by Image J of all mice was weekly monitored. Mice were sacrificed software. and plasma, liver, epididymal fat, and ileum were col- lected respectively. All tissue samples were frozen in liq- Statistical analysis uid nitrogen and stored at − 80 °C for further analysis. Statistical analysis was performed with GraphPad Prism 8.0 (GraphPad Software). Results were expressed as the Biochemical analysis mean ± standard error of mean (SEM) with at least three Plasma concentrations of LDL-C and HDL-C were deter- independent experiments. Statistical significance among mined using enzymatic reagent kits (Nanjing jiancheng, three groups was analyzed by one-way ANOVA with China). The levels of total bile acids of serum, feces, and Tukey’s post hoc test. Statistical significance was defined urine were measured using commercial assay kits (Nan- at p < 0.05. jing jiancheng, China). TC and TG concentrations in the liver were examined according to the manufacturer’s pro- Results tocols (Wako, Japan). l A ‑ rabinose reduces HFHSD‑induced body weight gain The HFHSD significantly increased body weight gain and index of liver and epididymal white adipose tissues com- Histological analysis pared with the control diet. In contrast to the HFHSD To determine the architecture changes and the size of group, the relative weight of liver and epididymal white lipid droplets in the liver, hematoxylin and eosin (H&E) adipose tissues exhibited a more obvious reduction in staining were performed as previously described [24]. l-arabinose-treated mice, which contributed to the Briefly, liver tissues were fixed in 10% neutral forma - higher body weight loss in the l-arabinose group. Fur - lin for 24  h. Then, after being embedded in paraffin and thermore, no significant difference in body weight gain sectioned at 5 μm thickness, tissue sections were stained and liver index was observed between the control group with H&E. The section images were observed under an and the l-arabinose group. However, the epididymal inverted light microscope (Axio Vert. A1, Carl Zeiss white adipose tissues index was significantly higher in the Microscopy GmbH, Germany). l-arabinose group than that of the control group. Quantitative real‑time PCR analysis (qRT‑PCR) l A ‑ rabinose improves lipid metabolism of HFHSD‑fed mice Total RNA was isolated from the liver and ileum tissues A significant rise in the serum level of LDL-C and a using RNAiso Plus (Takara, China). cDNA was synthe- decline in HDL-C content were observed in the mice sized using the Prime Script RT system (Takara, China). fed HFHSD compared with the control group. On Wang et al. Nutrition & Metabolism (2022) 19:30 Page 4 of 11 the contrary, l-arabinose administration significantly significantly increased the mRNA expressions of LDL-R, reduced the serum LDL-C content and increased HDL-C SR-B1, ABCG1, as well as ABCA1 in comparison with level (Fig.  2A). Furthermore, mice in the HFHSD-fed the HFHSD group (Fig. 3D). Taken together, these above group had significantly higher hepatic TC and TG lev - results demonstrated that l-arabinose could effectively els compared with the control group. The suppression inhibit cholesterol synthesis and enhance reverse choles- of hepatic TC and TG by l-arabinose was also appar - terol transport, thus lowering plasma and hepatic choles- ently observed (Fig.  2B). In addition, as shown in the terol levels. H&E staining of the liver tissue, the HFHSD-induced increases in lipid droplets, vacuoles, and disordered l A ‑ rabinose promotes the bile acid synthesis in the liver arrangement were attenuated by l-arabinose administra - Cholesterol catabolism to bile acids plays a key role in tion (Fig. 2C). The accumulation of hepatic lipids caused cholesterol homeostasis since bile acids are the major by HFHSD can lead to inflammation in the liver [26]. metabolites of cholesterol. We next determined the Therefore, the expression of hepatic inflammatory genes effects of l-arabinose on bile acid synthesis. As shown was also determined. As displayed in Fig.  2D, the inter- in Fig.  4A, l-arabinose markedly upregulated the mRNA vention of l-arabinose for 12 weeks inhibited the mRNA expression of CYP7A1 compared with the HFHSD group, level of tumor necrosis factor alpha (TNF-α) and and sig- while no significant changes were observed in other key nificantly increased interferon-γ (IFN-γ), interleukin-1β enzymes for classical or alternative bile acid synthe- (IL-1β) mRNA levels compared to those of the HFHSD- sis pathways including CYP27A1, CYP7B1, and sterol fed group. No significant change in interleukin-6 (IL-6) 12α-hydroxylase (CYP8B1). Moreover, the protein levels mRNA level was observed between the control group of CYP7A1 and CYP27A1 were elevated in the liver from and l-arabinose group under the same assay condition. HFHSD-fed mice treated with l-arabinose (Fig. 4B, C). These results indicated that l-arabinose improved lipid Negative feedback regulation plays an important role in metabolism disorder and hepatic steatosis induced by bile acid synthesis [27, 28]. The alternation of key genes HFHSD. related to negative feedback of hepatic bile acid synthe- sis, including FXR, small heterodimer partner (SHP), as l A ‑ rabinose suppresses hepatic cholesterol synthesis well as HNF-4α were presented in Fig.  4D. The mRNA and facilitates reverse cholesterol transport and protein expressions of FXR were downregulated in Given that l-arabinose administration could alleviate mice treated with l-arabinose. As the target gene of FXR, the elevated serum lipid levels and hepatic lipid accu- SHP was shown to repress bile acid synthesis through mulation caused by HFHSD, we further investigated inhibition of HNF-4α [29]. Similarly, l-arabinose supple - whether l-arabinose suppresses hepatic lipids synthe - mentation also lowered mRNA expression of SHP follow- sis, especially hepatic cholesterol. The mRNA expres - ing FXR in the liver, leading to increased expression of sions of the key genes controlling cholesterol metabolism HNF-4α at both protein and mRNA levels (Fig. 4E, F). In in the liver were measured. As shown in Fig.  3A, the addition, bile salt export pump (BSEP) is responsible for mRNA levels of HMGCR and SREBP-1c significantly hepatic bile acids efflux into canaliculi [18]. The mRNA increased in HFHSD-fed mice, which mediate the key expression of BSEP was higher in the liver of l-arabinose- step in cholesterol and triglycerides synthesis. l-Arab - treated mice than that of the HFHSD group, which might inose treatment significantly downregulated the mRNA be in response to increased bile acid synthesis (Fig. 4E). expressions of HMGCR and SREBP-1c compared with the HFHSD group. However, l-arabinose treatment l A ‑ rabinose enhances the bile acids excretion and reduces slightly increased the mRNA expressions of liver X the intestinal bile acid reabsorption receptor (LXR) and sterol regulatory element-binding Based on the results above, l-arabinose treatment could protein-2 (SREBP2) expression but no significant dif - enhance the cholesterol uptake from the circulation and ference was found compared with the HFHSD group. conversion to bile acids, so we speculated that l-ara - Moreover, similar modulation of the protein expressions binose might affect the reabsorption and excretion of of HMGCR and SREBP-1c was observed in mice treated bile acids. Therefore, we first measured the content of with l-arabinose (Fig.  3B, C). In addition, the expression bile acids in the feces and urine of mice. The excretion alternation of genes related to reverse cholesterol trans- of bile acids both in the HFHSD and l-arabinose group port in the liver, including low-density lipoprotein recep- was significantly higher than that of the control group. tor (LDL-R), scavenger receptor class B type 1 (SR-B1), Notably, l-arabinose treatment remarkably increased ATP binding cassette transporter G1 (ABCG1), and ATP bile acid excretion in comparison with the HFHSD group binding cassette transporter A1 (ABCA1) were detected. (Fig.  5A). Meanwhile, l-arabinose intervention slightly The results showed that l-arabinose intervention increased the content of bile acids in urine (Fig.  5B). In W ang et al. Nutrition & Metabolism (2022) 19:30 Page 5 of 11 contrast to the HFHSD group, l-arabinose treatment significantly decreased the level of total serum bile acids (Fig.  5C). Besides that, the level of fecal cholesterol was no significant difference among the three groups (Fig. 5D). In addition, l-arabinose had apparent effects on the reabsorption of bile acids in the small intestine. Regula- tory factors involved in the reabsorption of bile acids, including ASBT, I-BABP, and FXR, were downregulated in mice given l-arabinose compared to the HFHSD and control group (Fig.  5E). Consistently, l-arabinose treat - ment also reduced the protein expressions of ASBT and Fig. 1 Eec ff ts of l -arabinose on body weight gain and index of liver and epididymal white adipose tissues. Body weight gain (A), FXR in the ileum (Fig.  5F, G). The mRNA expression of index of liver (B), and index of epididymal white adipose tissues (C) fibroblast growth factor 15 (FGF15), as an FXR target in HFHSD-fed mice after 12 weeks treatment of l -arabinose. Data gene in the intestine, was largely attenuated in mice fed are shown as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001. WAT l-arabinose. Besides, l-arabinose had no obvious effect white adipose tissues, Ctrl control group, HFHSD HFHSD-fed group, on cholesterol absorption in the ileum (Additional file  1: HFHSD + L-Ara HFHSD-fed group treated with l -arabinose Fig. S1A). These results revealed that l-arabinose could promote the excretion of fecal bile acids by suppressing the reabsorption of intestinal bile acids. in this study, indicating l-arabinose exerted cholesterol- lowering effects to some extent (Fig.  2). Furthermore, the Discussion accumulation of lipids in the liver caused by consum- Hypercholesterolemia and hypertriglyceridemia are the ing HFHSD can give rise to hepatic inflammation [26]. main hallmarks of CVD [1]. Dietary intervention of cho- Our observation of regulatory effects of l-arabinose on lesterol-lowering functional foods of natural origin has inflammatory cytokines, by lowering TNF-α and increas - attracted much research interest in CVD prevention and ing IFN-γ, IL-1β mRNA levels in the liver, suggested treatment [3]. Several lines of evidence suggested that that l-arabinose supplementation may improve hepatic l-arabinose is involved in the improvement of lipid meta - inflammation induced by HFHSD. Similar observations bolic disorder and immune regulation [5]. Whereas the on inhibitory effects of l-arabinose on TC and TG levels contributions of l-arabinose to cholesterol metabolism and inflammation in the liver have been reported before were yet to be sufficiently evaluated. In the present study, [9]. hypercholesterolemic mice induced by HFHSD were l-Arabinose supplementation was reported to regu - used to assess the effects of l-arabinose on cholesterol late glucose homeostasis via inhibition of hepatic gluco- metabolism based on the regulation of bile acid metabo- neogenesis and improvement of insulin sensitivity, thus lism, and the possible molecular mechanism underly- suppressing elevated plasma glucose and insulin levels ing its hypocholesterolemic activity was preliminarily in metabolic disorder mice [31]. Since insulin promotes explored. cholesterol synthesis, supplementation of l-arabinose It has been reported that l-arabinose prevents and may help disrupt endogenous cholesterol biosynthesis. improves lipid metabolic disorder in other diet-induced HMGCR catalyzes the rate-limiting step of cholesterol hypercholesterolemia, thereby might play a role in diet- synthesis, and downregulation of HMGCR at protein induced hyperlipidemia, atherosclerosis, and CVD [30]. and mRNA levels was observed, which might be related Consistent with previous animal studies [9], mice in the to a lower level of hepatic cholesterol in the l-arab - l-arabinose group showed reductions in body weight inose group (Fig.  3A, B). In addition, our previous work gain, index of liver and epididymal white adipose com- observed that protective effects of l-arabinose on abnor - pared to those of the HFHSD-fed group, which con- mal gluconeogenesis were associated with the activation tributed to the improvement of hypercholesterolemia of AMP-activated protein kinase (AMPK). l-Arabinose (Fig.  1). The beneficial effects of l-arabinose on improv - promoted the activation of AMPK and reduced acetyl- ing serum lipid profiles by effectively lowering serum TC CoA carboxylase (ACC) activity, which helps to inhibit and TG content in HFHSD-fed mice had been displayed fatty acid synthesis, subsequently leading to the reduc- in our previous study [31]. As an extension of our previ- tion of hepatic lipid accumulation in metabolic disorder ous study, l-arabinose administration also prevented the mice caused by HFHSD [31]. Moreover, animal studies increases in serum LDL-C, hepatic TC, and TG levels, also showed that l-arabinose could reduce lipid levels by accompanied by elevated serum HDL-C concentration Wang et al. Nutrition & Metabolism (2022) 19:30 Page 6 of 11 Fig. 2 Eec ff ts of l -arabinose on lipid levels in the serum and liver of HFHSD-fed mice treated with or without l -arabinose for 12 weeks. Serum HDL-C and LDL-C levels (A) and hepatic TC and TG levels (B). Representative H&E-stained images of liver sections (magnification, × 400) (C). The mRNA expression of hepatic key inflammatory markers, TNF-α, IFN-γ, IL-1β, and IL-6, determined by RT-qPCR analysis (D). The mRNA expression levels were ## normalized to 18S and were shown relative to mice in the control group. Data are shown as mean ± SEM. p < 0.01 compared with the control ### group; p < 0.001 compared with the control group; *p < 0.05 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara, HFHSD-fed group treated with l -arabinose Fig. 3 l -Arabinose modulates hepatic cholesterol synthesis and facilitates reverse cholesterol transport. Eec ff ts of l -arabinose on the relative expression of LXR, HMGCR, SREBP-1c, and SREBP2 measured by qRT-PCR analysis (A) in the liver of HFHSD-fed mice treated with or without l -arabinose for 12 weeks. Eec ff ts of l -arabinose on protein levels of SREBP-1c and HMGCR in the liver (B) with densitometric quantification (C). Expression of key genes in reverse cholesterol transport in the liver (D). The mRNA and protein expression levels were normalized to 18S and GAPDH respectively and were shown relative to mice in the control group. Data are shown as mean ± SEM. p < 0.05 compared with the control ## group; p < 0.01 compared with the control group; *p < 0.05 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara HFHSD-fed group treated with l -arabinose W ang et al. Nutrition & Metabolism (2022) 19:30 Page 7 of 11 Fig. 4 l -Arabinose promotes bile acid synthesis in the liver. The hepatic mRNA expressions of CYP7A1, CYP27A1, CYP7B1, and CYP8B1 (A) in HFHSD-fed mice treated with or without l -arabinose for 12 weeks. The protein levels of CYP7A1, CYP27A1, and CYP7B1 in the liver (B) with densitometric quantification (C). HSP90 was used as an internal reference. The hepatic mRNA expressions of FXR, SHP, HNF-4α, and BSEP (D). The protein expression of hepatic FXR and HNF-4α (E) with densitometric quantification (F).GAPDH was used as an internal reference. Data are shown # ## as mean ± SEM. p < 0.05 compared with the control group; p < 0.01 compared with the control group; *p < 0.05 compared with the HFHSD-fed group; **p < 0.01 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara HFHSD-fed group treated with l -arabinose acting as an inhibitor of liver lipogenic enzymes, such as transport, which facilitates the removal of excess cho- ACC, ATP citrate-lyase, and fatty acid synthase in rats lesterol from peripheral tissue back to the liver for fur- with high dietary sucrose [30]. Besides, Hao et  al. found ther metabolism. ABCG1 mainly mediates intracellular that l-arabinose dramatically ameliorated metabolic syn - cholesterol efflux to HDL, while ABCA1 promotes cho - drome by upregulating the genes participated in energy lesterol flow to apolipoprotein A1 [37]. Expressions of expenditure pyruvate dehydrogenase kinase 4 (PDK4) ABCG1 and ABCA1 were elevated in response to l-ara - and carnitine palmitoyltransferase 1α (CPT-1α) and binose intervention, which in line with the increase in downregulating adipogenesis genes ACC [8]. Our studies plasma HDL-C levels, therefore preventing excessive were also in line with these conclusions. cellular lipids accumulation (Fig.  3D). However, the reg- Concentrations of circulating cholesterol, including ulatory effects of l-arabinose on the reverse cholesterol LDL-C and HDL-C, were governed by reverse cholesterol transport process in peripheral tissue, especially in mac- transport, in which cholesterol from peripheral tissues is rophages, remain to be explored in our future research. transported to the liver for subsequent hepatic catabo- Our data revealed that the cholesterol-lowering effect of lism into bile and excretion [32, 33]. LDL-R and SR-B1 l-arabinose may be attributed in part to its role in sup - are two key receptors in this process [34]. LDL-R medi- pressing cholesterol synthesis and promoting reverse ates the removal of plasma LDL-C, whereas SR-B1, as cholesterol transport. the high-affinity receptor of HDL, is responsible for the Bile acid reabsorption and cholesterol absorption in selective uptake of HDL lipids [35, 36]. Upregulations of the small intestine are closely related to maintaining LDL-R and SR-B1 expression were observed after l-ara - cholesterol homeostasis, and lowering cholesterol func- binose treatment, which was associated with decreased tion of other substances is closely linked to these two plasma cholesterol level (Fig.  3D). Besides, ABCG1 and pathways [23, 38]. For instance, the underlying mecha- ABCA1 contribute to the process of reverse cholesterol nisms for the hypocholesterolemic activity of β-sitosterol Wang et al. Nutrition & Metabolism (2022) 19:30 Page 8 of 11 Fig. 5 l -Arabinose enhances the bile acids excretion and reduces intestinal bile acids reabsorption. Total bile acids content in the feces (A), urine (B) and serum (C), and fecal cholesterol level (D) in HFHSD-fed mice treated with or without l -arabinose for 12 weeks. The ileal mRNA expressions of ASBT, I-BABP, FXR, and FGF15 determined by qRT-PCR analysis (E). The ileal protein expressions of FXR, ASBT, and I-BABP determined by western # ## blotting (F) with densitometric quantification (G). Data are shown as mean ± SEM. p < 0.05 compared with the control group; p < 0.01 compared with the control group; *p < 0.05 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara HFHSD-fed group treated with l -arabinose laurate involve these two pathways mediated by reducing shown in Additional file  1: Fig. S1A, the less relevance of ASBT and I-BABP levels and downregulating intestinal cholesterol absorption to the hypocholesterolemic effects niemann-pick c1-like protein 1 (NPC1L1) respectively, of l-arabinose was observed as indicated by unchanged therefore, increasing the excretion of fecal bile acids and expression of related genes, which was consistent with cholesterol [39]. We next explored whether l-arabinose the results of fecal cholesterol content in the l-arabinose maintains cholesterol homeostasis by regulating bile group. Furthermore, previous studies have confirmed acid reabsorption and cholesterol absorption. Most bile that l-arabinose could protect the intestinal barrier from acids are reabsorbed into the intestinal epithelial cells by dextran sodium sulfate-induced colitis and gliadins- ASBT mainly localized at the enterocyte brush border, induced damage [6, 42]. In the present study, l-arabinose then transported to the basolateral membrane with the intervention could increase the mRNA expression of assistance of I-BABP, and finally, efflux into the portal tight junction proteins, mainly including ZO-1, occludin, blood and transport to the liver [40, 41]. Further research and claudin, which contributed to maintaining intestinal found that the inhibition of bile acid reabsorption by barrier integrity and epithelial barrier function (Addi- l-arabinose also occurred via depressing the expression tional file 1: Fig. S1B). of ASBT and I-BABP in the ileum, which was consistent As the major end product of cholesterol catabolism, with the results of increasing the fecal bile acids level and reabsorption of bile acid in the small intestine could lower serum bile acid content in the l-arabinose group influence the process of hepatic bile acid synthesis due (Fig.  5E, F). Besides, the expressions of key regulatory to enterohepatic circulation, consequently adjusting the factors related to cholesterol absorption and excretion in homeostasis of hepatic cholesterol [17]. As mentioned the ileum, including NPC1L1, microsomal triacylglycerol above, l-arabinose enhanced the excretion of fecal bile transport protein (MTP), ATP binding cassette transport- acids by reducing the bile acids reabsorption in the ileum, ers 5 and 8 (ABCG5 and ABCG8), acyl CoA cholesterol which might lead to hepatic cholesterol depletion. As acyltransferase 2 (ACAT2), were determined to explore expected, the impediment to enterohepatic circulation the effect of l-arabinose on cholesterol absorption. As of bile acids promoted hepatic bile acid synthesis in the W ang et al. Nutrition & Metabolism (2022) 19:30 Page 9 of 11 l-arabinose group, mainly through the CYP7A1 medi - FXR on hepatic bile acid synthesis was reserved by l-ara - ated classical pathway, to maintain the balance of the binose, whereas its exact mechanisms are still needed bile acids pool (Fig.  4A, B). Hepatic CYP7A1 expression to be investigated. Several studies identified inactivating was downregulated in insulin-resistant mice [43], and FXR-mediated negative feedback mechanism by which the increase in CYP7A1 expression is consistent with cholesterol-lowering functional foods accelerate bile acid our previous study showing that l-arabinose relieved synthesis [46, 47]. For instance, Geniposide enhanced hepatic insulin-resistant state induced by HFHSD or the hepatic synthesis of bile acids via FXR-mediated high sucrose diet (HSD). As a critical regulatory fac- negative feedback inhibition of bile acids, leading to the tor for bile acid synthesis and transport, FXR has a vital increase in cholesterol catabolism and reverse cholesterol influence on the enterohepatic circulation of bile acids, transport [24]. Consequently, it was speculated that the thus regulating the homeostasis of hepatic cholesterol cholesterol-lowering effect of l-arabinose was in part [44, 45]. l-Arabinose promoted bile acid synthesis in the ascribed to diminishing the reabsorption of intestinal bile present work, and we suspected that negative feedback acids, and then promoted the conversion of hepatic cho- regulation of bile acids mediated by FXR might be acti- lesterol into bile acids (Fig. 6). vated. However, as reflected by our results, the expres - sion of FXR in the ileum was decreased accompanied by Conclusions the lower level of fibroblast growth factor 15 (FGF15). In summary, we confirmed that hypercholester - Moreover, the expression of FXR and its target gene, olemia induced by HFHSD in mice could be ame- SHP, were also inhibited in the liver with a subsequent liorated by l -arabinose dietary intervention. The increase in expression of CYP7A1 at both mRNA and beneficial effects of l -arabinose on HFHSD-induced protein levels after l-arabinose treatment (Fig.  5E, F). hypercholesterolemia were associated with improved Our data supported that the negative regulatory effect of cholesterol homeostasis via the modulation of bile acid Fig. 6 Graphical abstract of the effects of l -arabinose on improving hypercholesterolemia in HFSD-fed mice. l -Arabinose not only inhibited cholesterol synthesis but also facilitated cholesterol transport from peripheral tissue to the liver, so as to reduce circulating cholesterol. Moreover, dietary administration with l -arabinose had beneficial effects on bile acids homeostasis by reducing the reabsorption of bile acids and promoting hepatic bile acid synthesis, thus accelerating the excretion of bile acids while enhancing the decomposition of cholesterol into bile acids, ultimately facilitating cholesterol homeostasis and alleviating hypercholesterolemia. Arrows (↑) represent upregulation of protein or mRNA expression. Arrows (↓) represent downregulation Wang et al. Nutrition & Metabolism (2022) 19:30 Page 10 of 11 Declarations metabolism. Our work provides insight into the devel- opment and application of functional foods containing Ethics approval and consent to participate l -arabinose against hypercholesterolemia, but the reg- All animal protocols and procedures were approved by the Laboratory Animal Ethics Committee of Jiangnan University (University JN. No20190315c0320630 ulatory mechanism needs to be further investigated. [26]). Consent for publication Abbreviations Not applicable. ABCA1: ATP binding cassette transporter A1; ABCG1: ATP binding cas- sette transporter G1; ASBT: Apical sodium-dependent bile salt transporter; Competing interest BSEP: Bile salt export pump; CVD: Cardiovascular diseases; CYP7A1: Cho- The authors declare that they have no competing interests. lesterol 7α-hydroxylase; CYP7B1: Oxysterol 7α-hydroxylase; CYP8B1: Sterol 12α-hydroxylase; CYP27A1: Mitochondrial sterol 27-hydroxylase; FXR: Author details Farnesoid X receptor; GAPDH: Glyceraldehyde-3-phosphate dehydroge- State Key Laboratory of Food Science and Technology, School of Food nase; HDL-C: High-density lipoprotein cholesterol; HMGCR : 3-Hydroxy- Science and Technology, Jiangnan University, Wuxi 214122, China. Col- 3-methylglutaryl-CoA reductase; HNF-4α: Hepatocyte nuclear factor-4α; lege of Cooking Science and Technology, Jiangsu College of Tourism, HFHSD: High-fat-high-sucrose diet; HSP90: Heat shock protein 90; I-BABP: Yangzhou 225000, China. China National Institute of Standardization, No. 4 Ileal-bile acid-binding protein; IFN-γ: Interferon-γ; IL-6: Interleukin-6; IL-1β: Zhichun Road, Haidian District, Beijing, China. Interleukin-1β; LDL-C: Low-density lipoprotein cholesterol; LDL-R: Low density lipoprotein receptor; LRH-1: Liver receptor homolog-1; LXR: Liver X receptor; Received: 25 January 2022 Accepted: 29 March 2022 SHP: Small heterodimer partner; SR-B1: Scavenger receptor class B type 1; SREBP-1c: Sterol regulatory element binding protein-1c; SREBP2: Sterol regula- tory element-binding protein-2; TC: Total cholesterol; TG: Triglyceride; TNF-α: Sumor necrosis factor-α. References Supplementary Information 1. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, et al. Heart disease The online version contains supplementary material available at https:// doi. and stroke statistics—2021 update. Circulation. 2021;143:e254–743. org/ 10. 1186/ s12986- 022- 00662-8. 2. Archundia Herrera MC, Subhan FB, Chan CB. Dietary Patterns and Car- diovascular Disease Risk in People with Type 2 Diabetes. Curr Obes Rep. 2017;6:405–13. Additional file 1. Table S1: Primer Sequences. Fig. S1: Relative mRNA 3. Chen Z-Y, Jiao R, Ma KY. Cholesterol-lowering nutraceuticals and func- expression of genes involved in cholesterol metabolism in the small intes- tional foods. J Agric Food Chem. 2008;56:8761–73. tine of HFHSD-fed mice treated with or without L-arabinose for 12 weeks 4. Ouimet M, Barrett TJ, Fisher EA. HDL and reverse cholesterol transport. (A). The mRNA expression levels of ZO-1, occludin, and claudin in ileum Circ Res. 2019;124:1505–18. sections (B). Data are shown as mean ± SEM. p < 0.05 compared with the ## ### 5. Fehér C. Novel approaches for biotechnological production and applica- control group; p < 0.01 compared with the control group; p < 0.001 tion of l -arabinose. J Carbohydr Chem. 2018;37:251–84. compared with the control group; *p < 0.05 compared with the HFHSD- 6. Li Y, Pan H, Liu J-x, Li T, Liu S, Shi W, Sun C, Fan M, Xue L, Wang Y, et al. fed group. Ctrl: control group; HFHSD: HFHSD-fed group; HFHSD+L-Ara: l -Arabinose inhibits colitis by modulating gut microbiota in mice. J Agric HFHSD-fed group treated with L-arabinose. Fig. S2: Serum FFA level Food Chem. 2019;67:13299–306. in HFHSD-fed mice treated with or without L-arabinose for 12 weeks. 7. Krog-Mikkelsen I, Hels O, Tetens I, Holst JJ, Andersen JR, Bukhave K. The **p < 0.01 compared with the HFHSD-fed group. Ctrl: control group; effects of l -arabinose on intestinal sucrase activity: dose-response studies HFHSD: HFHSD-fed group; HFHSD+L-Ara: HFHSD-fed group treated with in vitro and in humans. Am J Clin Nutr. 2011;94:472–8. L-arabinose. 8. Hao L, Lu X, Sun M, Li K, Shen L, Wu T. Protective effects of l -arabinose in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. Acknowledgements Food Nutr Res. 2015;59:28886. None. 9. Zhao L, Wang Y, Zhang G, Zhang T, Lou J, Liu J. l -Arabinose elicits gut- derived hydrogen production and ameliorates metabolic syndrome in Author contributions C57BL/6J mice on high-fat-diet. Nutrients. 2019;11:3054. YW and YL designed the study. YW, JJZ, QL, JXL, YJS, and KLZ conducted the 10. Shibanuma K, Degawa Y, Houda K. Determination of the transient period research and analyzed the data. YW and YL wrote the initial paper. MCF, HFQ, of the EIS complex and investigation of the suppression of blood glucose and LW revised the paper. LW provided research funding. All authors read and levels by l -arabinose in healthy adults. Eur J Nutr. 2011;50:447–53. approved the final manuscript. 11. Seri K, Sanai K, Matsuo N, Kawakubo K, Xue C, Inoue S. l-Arabinose selectively inhibits intestinal sucrase in an uncompetitive manner Funding and suppresses glycemic response after sucrose ingestion in animals. This work was supported by the National Natural Science Foundation of Metabolism. 1996;45:1368–74. China (31900841, 32071166), the Young Eliet Scientists Sponsorship Program 12. Luo J, Yang H, Song B-L. Mechanisms and regulation of cholesterol by CAST (2020QNRC001), the Research and Development Program of homeostasis. Nat Rev Mol Cell Biol. 2020;21:225–45. Wuxi (N20203005), the Research and Development Program of Tianchang 13. Chang T-Y, Chang CCY, Ohgami N, Yamauchi Y. Cholesterol sensing, traf- ( TZY202002), the "Qing Lan Project" of Jiangsu Province, the Open Project ficking, and esterification. Annu Rev Cell Dev Biol. 2006;22:129–57. Program of China-Canada Joint Lab of Food Nutrition and Health, Beijing Tech- 14. Yu X-H, Zhang D-W, Zheng X-L, Tang C-K. Cholesterol transport system: nology and Business University (BTBU), and the Fundamental Research Funds an integrated cholesterol transport model involved in atherosclerosis. for the Central Universities (JUSRP221001). Prog Lipid Res. 2019;73:65–91. 15. Gil-Ramirez A, Caz V, Smiderle FR, Martin-Hernandez R, Largo C, Tab- Availability of data and materials ernero M, Marin FR, Iacomini M, Reglero G, Soler-Rivas C. Water-soluble The datasets underlying this article are available from the corresponding compounds from lentinula edodes influencing the HMG-CoA reductase author on reasonable request. W ang et al. Nutrition & Metabolism (2022) 19:30 Page 11 of 11 activity and the expression of genes involved in the cholesterol metabo- metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet. Food lism. J Agric Food Chem. 2016;64:1910–20. Nutr Res. 2019;63:66. 16. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. 39. Chen S, Wang R, Cheng M, Wei G, Du Y, Fan Y, Li J, Li H, Deng Z. Serum Annu Rev Biochem. 2003;72:137–74. cholesterol-lowering activity of beta-sitosterol laurate is attributed to the 17. van de Peppel IP, Verkade HJ, Jonker JW: Metabolic consequences of ileal reduction of both cholesterol absorption and bile acids reabsorption in interruption of the enterohepatic circulation of bile acids. Am J Physiol hamsters. J Agric Food Chem. 2020;68:10003–14. Gastrointest Liver Physiol. 2020;319:G619-25. 40. Li M, Wang Q, Li Y, Cao S, Zhang Y, Wang Z, Liu G, Li J, Gu B. Apical sodium- 18. de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids dependent bile acid transporter, drug target for bile acid related diseases in metabolism. Cell Metab. 2013;17:657–69. and delivery target for prodrugs: current and future challenges. Pharma- 19. Neimark E, Chen F, Li X, Shneider BL. Bile acid–induced negative feed- col Therap. 2020;212:107539. back regulation of the human ileal bile acid transporter. Hepatology. 41. Badiee M, Tochtrop GP. Bile acid recognition by mouse ileal bile acid bind- 2004;40:149–56. ing protein. ACS Chem Biol. 2017;12(12):3049–56. 20. Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal absorption 42. Wang Y, Sun J, Xue L, Liu J, Nie C, Fan M, Qian H, Zhang D, Ying H, Li Y, of bile acids in health and disease. Compr Physiol. 2019;10:21–56. Wang L. l-Arabinose attenuates gliadin-induced food allergy via regula- 21. Li-Hawkins J, Gåfvels M, Olin M, Lund EG, Andersson U, Schuster G, tion of Th1/Th2 balance and upregulation of regulatory T cells in mice. J Björkhem I, Russell DW, Eggertsen G. Cholic acid mediates nega- Agric Food Chem. 2021;69:3638–46. tive feedback regulation of bile acid synthesis in mice. J Clin Investig. 43. Kim H, Bartley GE, Rimando AM, Yokoyama W. Hepatic gene expression 2002;110:1191–200. related to lower plasma cholesterol in hamsters fed high-fat diets sup- 22. Yang Y, Sun Q, Xu X, Yang X, Gao Y, Sun X, Zhao Y, Ding Z, Ge W, Cheng plemented with blueberry peels and peel extract. J Agric Food Chem. R, Zhang J. Oral administration of succinoglycan riclin improves 2010;58:3984–91. diet-induced hypercholesterolemia in mice. J Agric Food Chem. 44. Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. 2019;67:13307–17. Mol Cell Endocrinol. 2013;368:17–29. 23. Li D, Cui Y, Wang X, Liu F, Li X. Apple polyphenol extract improves high-fat 45. Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of diet-induced hepatic steatosis by regulating bile acid synthesis and gut metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, microbiota in C57BL/6 male mice. J Agric Food Chem. 2021;69:6829–41. and nonalcoholic fatty liver disease. Gastroenterology. 2017;152:1679- 24. Liu J, Li Y, Sun C, Liu S, Yan Y, Pan H, Fan M, Xue L, Nie C, Zhang H, et al. 1694.e1673. Geniposide reduces cholesterol accumulation and increases its excretion 46. Zeng BB, Zhang LY, Chen C, Zhang TT, Xue CH, Yanagita T, Li ZJ, Wang YM. by regulating the FXR-mediated liver-gut crosstalk of bile acids. Pharma- Sea cucumber sterol alleviates the lipid accumulation in high-fat-fructose col Res. 2020;152:104631. diet fed mice. J Agric Food Chem. 2020;68:9707–17. 25. Liu J, Nie C, Xue L, Yan Y, Liu S, Sun J, Fan M, Qian H, Ying H, Wang L, Li Y. 47. Duan R, Guan X, Huang K, Zhang Y, Li S, Xia J, Shen M. Flavonoids from Growth hormone receptor disrupts glucose homeostasis via promoting whole-grain oat alleviated high-fat diet-induced hyperlipidemia via and stabilizing retinol binding protein 4. Theranostics. 2021;11:8283–300. regulating bile acid metabolism and gut microbiota in mice. J Agric Food 26. Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: Chem. 2021;69:7629–40. emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48:677–85. 27. Kong B, Wang L, Chiang JY, Zhang Y, Klaassen CD, Guo GL. Mechanism Publisher’s Note of tissue-specific farnesoid X receptor in suppressing the expression of Springer Nature remains neutral with regard to jurisdictional claims in pub- genes in bile-acid synthesis in mice. Hepatology. 2012;56:1034–43. lished maps and institutional affiliations. 28. Chiang JYL. Negative feedback regulation of bile acid metabolism: impact on liver metabolism and diseases. Hepatology. 2015;62:1315–7. 29. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000;6:517–26. 30. Osaki S, Kimura T, Sugimoto T, Hizukuri S, Iritani N. l -Arabinose feeding prevents increases due to dietary sucrose in lipogenic enzymes and triacylglycerol levels in rats. J Nutr. 2001;131:796–9. 31. Wang Y, Guan Y, Xue L, Liu J, Yang Z, Nie C, Yan Y, Liu S, Sun J, Fan M, et al. l-Arabinose suppresses gluconeogenesis through modulating AMP-activated protein kinase in metabolic disorder mice. Food Funct. 2021;12:1745–56. 32. Frambach SJCM, de Haas R, Smeitink JAM, Rongen GA, Russel FGM, Schir- ris TJJ. Brothers in arms: ABCA1- and ABCG1-mediated cholesterol efflux as promising targets in cardiovascular disease treatment. Pharmacol Rev. 2020;72:152. 33. Kennedy MA, Barrera GC, Nakamura K, Baldán Á, Tarr P, Fishbein MC, Frank J, Francone OL, Edwards PA. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : Metab. 2005;1:121–31. 34. Strickland DK, Gonias SL, Argraves WS. Diverse roles for the LDL receptor fast, convenient online submission family. Trends Endocrinol Metab. 2002;13:66–74. thorough peer review by experienced researchers in your field 35. Shen W-J, Azhar S, Kraemer FB. SR-B1: a unique multifunctional receptor for cholesterol influx and efflux. Annu Rev Physiol. 2018;80:95–116. rapid publication on acceptance 36. Linton MF, Tao H, Linton EF, Yancey PG. SR-BI: a multifunctional receptor support for research data, including large and complex data types in cholesterol homeostasis and atherosclerosis. Trends Endocrinol Metab. • gold Open Access which fosters wider collaboration and increased citations 2017;28:461–72. 37. Dan L, Bart Z, Ying M, Illiana V, Berkel T. ATP-binding cassette transport- maximum visibility for your research: over 100M website views per year ers A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis. Curr Drug Targets. At BMC, research is always in progress. 2011;12:647–60. Learn more biomedcentral.com/submissions 38. Han S, Zhang W, Zhang R, Jiao J, Fu C, Tong X, Zhang W, Qin L. Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nutrition & Metabolism Springer Journals

l-Arabinose improves hypercholesterolemia via regulating bile acid metabolism in high-fat-high-sucrose diet-fed mice

Loading next page...
 
/lp/springer-journals/l-arabinose-improves-hypercholesterolemia-via-regulating-bile-acid-L1ubvk6s58

References (63)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2022
eISSN
1743-7075
DOI
10.1186/s12986-022-00662-8
Publisher site
See Article on Publisher Site

Abstract

Background: Hypercholesterolemia is closely associated with an increased risk of cardiovascular diseases. l -Arab- inose exhibited hypocholesterolemia properties, but underlying mechanisms have not been sufficiently investigated. This study aimed to elucidate the mechanisms of l -arabinose on hypocholesterolemia involving the enterohepatic circulation of bile acids. Methods: Thirty six-week-old male mice were randomly divided into three groups: the control group and the high- fat-high-sucrose diet (HFHSD)-fed group were gavaged with distilled water, and the l -arabinose-treated group were fed HFHSD and received 400 mg/kg/day l -arabinose for 12 weeks. Serum and liver biochemical parameters, serum and fecal bile acid, cholesterol and bile acid metabolism-related gene and protein expressions in the liver and small intestine were analyzed. Results: l -Arabinose supplementation significantly reduced body weight gain, lowered circulating low-density lipo - protein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C) levels, and efficiently allevi- ated hepatic inflammation and lipid accumulations in HFHSD-fed mice. l -Arabinose inhibited cholesterol synthesis via downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Additionally, l -arabinose might facilitate reverse cholesterol transport, evidenced by the increased mRNA expressions of low-density lipoprotein receptor (LDL-R) and scavenger receptor class B type 1 (SR-B1). Furthermore, l -arabinose modulated ileal reabsorption of bile acids mainly through downregulation of ileal bile acid-binding protein (I-BABP) and apical sodium-dependent bile acid transporter (ASBT ), resulting in the promotion of hepatic synthesis of bile acids via upregulation of cholesterol- 7α-hydroxylase (CYP7A1). Conclusions: l -Arabinose supplementation exhibits hypocholesterolemic effects in HFHSD-fed mice primarily due to regulation of bile acid metabolism-related pathways. Keywords: l -Arabinose, Cholesterol metabolism, Bile acid, Hypercholesterolemia Introduction Cardiovascular diseases (CVD) are the leading deter- minant of death worldwide, and abnormal cholesterol metabolism is strongly associated with an elevated risk *Correspondence: liyan0520@jiangnan.edu.cn; wangli@jiangnan.edu.cn of CVD [1]. Along with unhealthy dietary habits and life- Yu Wang, Jiajia Zhao and Qiang Li have contributed equally to this work styles, such as excessive intake of high-fat-high-sucrose State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China diet (HFHSD), the prevalence of hypercholesterolemia Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Nutrition & Metabolism (2022) 19:30 Page 2 of 11 increases year by year [2]. Epidemiological evidence has [17]. Bile acid synthesis includes the classical path- demonstrated that ascending levels of total cholesterol way and alternative pathway mediated by cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase contribute to the development of CVD, while the high- (CYP27A1) respectively, and is modulated by nuclear density lipoprotein cholesterol (HDL-C) is related to receptor farnesoid X receptor (FXR)-mediated negative decreased risk for CVD events [3, 4]. Thus, amelioration feedback regulation [18, 19]. Moreover, the reabsorp- or reversion of the progression of hypercholesterolemia tion of intestinal bile acids, which enables bile acids to might be the target of CVD prevention. However, pro- return to the liver and maximizes the use of it through longed administration of drugs for hypercholesterolemia enterohepatic circulation, also has a vital influence on may induce undesirable side effects [3]. Therefore, dietary cholesterol homeostasis [20, 21]. Previous studies have intake of cholesterol-lowering natural products has been clearly revealed that the hypocholesterolemic action of considered as potential candidates suitable for patients functional foods supplement is closely related to enter- with low or moderate hypercholesterolemia. ohepatic circulation of bile acids [22, 23]. Therefore, it l-Arabinose, an aldopentose in plants, usually is necessary to consider the regulatory effect of l -ara- extracted from corn cobs, beet pulp, or wheat bran, binose on cholesterol metabolism from the perspective has been proved to possess benefits in alleviating lipid of bile acid metabolism. metabolic disorder, improving insulin resistance, and Although previous studies have shown the hypocho- anti-inflammation [5, 6]. Previous studies have demon- lesterolemia properties of l -arabinose, how l -arabinose strated that l-arabinose effectively alleviates hyperlipi - improved cholesterol homeostasis via the modulation demia caused by the high consumption of dietary fat and of bile acid metabolism needs further research. In the sucrose [7]. For instance, l-arabinose treatment showed present study, hypercholesterolemic mice induced by cholesterol-lowering properties according to lowering HFHSD were applied to assess the effect and possible triglyceride (TG), TC, and LDL-C levels and increasing molecular mechanisms of cholesterol-lowering in the HDL-C levels in metabolic syndrome rats induced by a regulation of bile acid metabolism after l -arabinose high-carbohydrate, high-fat (HCHF) diet [8]. Recently, supplementation. The results showed that dietary it was reported that l-arabinose could alleviate high-fat- l -arabinose exhibited effects on alleviating HFHSD- diet-induced metabolic syndrome in mice by modulat- induced hypercholesterolemia through regulating bile ing the expression of genes governing lipid metabolism acid metabolism. and mitochondrial function, effectively restoring altered lipid profile both in the serum and liver [9]. Furthermore, the major mechanism underlying l-arabinose’s hypolipi - Methods demic effects may be attributed to inhibition of intestinal Materials and chemicals sucrase activity, thereby delaying sucrose utilization, and l-Arabinose was obtained from Sigma-Aldrich consequently reducing lipogenesis [7, 10, 11]. Although (W325512). LDL-C and HDL-C enzymatic reagent the intervention of l-arabinose exhibited cholesterol- kits were purchased from Nanjing Jiancheng Bioengi- lowering effects, the underlying mechanisms remain to neering Institute (Nanjing, China). LabAssay TG and be further investigated. LabAssay TC were obtained from WAKO ( Japan). Total Maintaining cholesterol homeostasis is crucial for bile acid assay kit was purchased from Huijia Biotech- metabolic health. Cholesterol metabolism comprises nology (Huijia Biotechnology, China). RNAiso Plus and a tightly regulated process of cholesterol biosynthesis, Prime Script RT system were purchased from Takara absorption, transport, and catabolism, which involves Biomedical Technology (Beijing, China). Primary diverse transporters, enzymes, and receptor proteins antibodies against 3-hydroxy-3-methylglutaryl-CoA [12, 13]. Both inhibition of cholesterol synthesis in reductase (HMGCR), sterol regulatory element bind- the liver and acceleration of reverse transport from ing protein-1c (SREBP-1c), and bile acid transporter peripheral tissue to liver, representing major hypocho- (ASBT) were purchased from Proteintech (IL, USA). lesterolemic mechanisms, are beneficial to lowering Antibodies against CYP7A1, hepatic nuclear factor 4α circulating cholesterol levels [14, 15]. Since choles- (HNF-4α), and Ileal-bile acid-binding protein (I-BABP) terol is the precursor to bile acid synthesis in the liver, were purchased from Santa Cruz Biotechnology (CA, no doubt regulating cholesterol homeostasis is influ - USA). Antibodies against CYP27A1 and oxysterol enced profoundly by bile acid metabolism [16]. The 7α-hydroxylase (CYP7B1) were acquired from Abcam enterohepatic circulation of bile acids contains a com- (Cambridge, UK). Antibodies against FXR, GAPDH, plex network of hepatic bile acid synthesis and excre- and HSP90 were purchased from Cell Signaling Tech- tion, intestinal reabsorption, and transport to the liver nology (MA, USA). W ang et al. Nutrition & Metabolism (2022) 19:30 Page 3 of 11 Animal qRT-PCR was performed using the ABI 7900 RT-PCR C57BL/6  J male mice (6  weeks old, 18–20  g) were pur- system (Applied Biosystem, USA) for the expression lev- chased from Shanghai SLAC Laboratory Animal Co., els of genes related to cholesterol and bile acid metabo- Ltd (Shanghai, China). All mice were kept in specific lism. The relative mRNA expression level was normalized pathogen-free conditions (24 ± 2 °C, 60% relative humid- to 18S. The sequences of qRT-PCR primers were shown ity, and 12  h light/dark cycle) and given food and water in Additional file 1: Table S1. ad  libitum. All animal protocols and procedures were performed following the approval from the Laboratory Western blot analysis Animal Ethics Committee of Jiangnan University (Uni- Western blot analysis was performed according to the versity JN. No20190315c0320630 [26]). After 1  week of method described previously [25]. Liver or ileum tissues acclimation, thirty mice were randomly divided into the were homogenized using RIPA lysis buffer (Beyotime, control group, the high-fat-high-sucrose diet-fed group Shanghai, China). After complete lysis and collection of (HFHSD group), and HFHSD fed mice receiving l-ara - the supernatant, the protein concentration was deter- binose (HFHSD + L-Ara group, Sigma-Aldrich, admin- mined using the BCA protein assay reagent (Beyotime, istrated intragastrically with 400  mg/kg/day l-arabinose Shanghai, China). 30 μg of each protein sample was sepa- for 12  weeks). The selection of dose was based on pre - rated on 10% SDS-PAGE and then transferred to polyvi- vious research [6]. The control and HFHSD groups were nylidene fluoride (PVDF) membranes. The membranes intragastrically administrated with same volume of dis- were incubated with corresponding primary antibodies tilled water per day. Mice in HFHSD and HFHSD + L-Ara overnight at 4  °C. Subsequently, membranes were incu- group received a high-fat diet (Research Diets, D12492), bated with appropriate secondary antibodies at room accompanied by a 10% glucose solution (Sigma-Aldrich) temperature for 1.5  h. The protein expression level was for 12  weeks. Urine and feces were collected and stored normalized to the HSP90 or GAPDH. The quantification at − 80 °C at the end of the experiments. The body weight of the protein band intensity was determined by Image J of all mice was weekly monitored. Mice were sacrificed software. and plasma, liver, epididymal fat, and ileum were col- lected respectively. All tissue samples were frozen in liq- Statistical analysis uid nitrogen and stored at − 80 °C for further analysis. Statistical analysis was performed with GraphPad Prism 8.0 (GraphPad Software). Results were expressed as the Biochemical analysis mean ± standard error of mean (SEM) with at least three Plasma concentrations of LDL-C and HDL-C were deter- independent experiments. Statistical significance among mined using enzymatic reagent kits (Nanjing jiancheng, three groups was analyzed by one-way ANOVA with China). The levels of total bile acids of serum, feces, and Tukey’s post hoc test. Statistical significance was defined urine were measured using commercial assay kits (Nan- at p < 0.05. jing jiancheng, China). TC and TG concentrations in the liver were examined according to the manufacturer’s pro- Results tocols (Wako, Japan). l A ‑ rabinose reduces HFHSD‑induced body weight gain The HFHSD significantly increased body weight gain and index of liver and epididymal white adipose tissues com- Histological analysis pared with the control diet. In contrast to the HFHSD To determine the architecture changes and the size of group, the relative weight of liver and epididymal white lipid droplets in the liver, hematoxylin and eosin (H&E) adipose tissues exhibited a more obvious reduction in staining were performed as previously described [24]. l-arabinose-treated mice, which contributed to the Briefly, liver tissues were fixed in 10% neutral forma - higher body weight loss in the l-arabinose group. Fur - lin for 24  h. Then, after being embedded in paraffin and thermore, no significant difference in body weight gain sectioned at 5 μm thickness, tissue sections were stained and liver index was observed between the control group with H&E. The section images were observed under an and the l-arabinose group. However, the epididymal inverted light microscope (Axio Vert. A1, Carl Zeiss white adipose tissues index was significantly higher in the Microscopy GmbH, Germany). l-arabinose group than that of the control group. Quantitative real‑time PCR analysis (qRT‑PCR) l A ‑ rabinose improves lipid metabolism of HFHSD‑fed mice Total RNA was isolated from the liver and ileum tissues A significant rise in the serum level of LDL-C and a using RNAiso Plus (Takara, China). cDNA was synthe- decline in HDL-C content were observed in the mice sized using the Prime Script RT system (Takara, China). fed HFHSD compared with the control group. On Wang et al. Nutrition & Metabolism (2022) 19:30 Page 4 of 11 the contrary, l-arabinose administration significantly significantly increased the mRNA expressions of LDL-R, reduced the serum LDL-C content and increased HDL-C SR-B1, ABCG1, as well as ABCA1 in comparison with level (Fig.  2A). Furthermore, mice in the HFHSD-fed the HFHSD group (Fig. 3D). Taken together, these above group had significantly higher hepatic TC and TG lev - results demonstrated that l-arabinose could effectively els compared with the control group. The suppression inhibit cholesterol synthesis and enhance reverse choles- of hepatic TC and TG by l-arabinose was also appar - terol transport, thus lowering plasma and hepatic choles- ently observed (Fig.  2B). In addition, as shown in the terol levels. H&E staining of the liver tissue, the HFHSD-induced increases in lipid droplets, vacuoles, and disordered l A ‑ rabinose promotes the bile acid synthesis in the liver arrangement were attenuated by l-arabinose administra - Cholesterol catabolism to bile acids plays a key role in tion (Fig. 2C). The accumulation of hepatic lipids caused cholesterol homeostasis since bile acids are the major by HFHSD can lead to inflammation in the liver [26]. metabolites of cholesterol. We next determined the Therefore, the expression of hepatic inflammatory genes effects of l-arabinose on bile acid synthesis. As shown was also determined. As displayed in Fig.  2D, the inter- in Fig.  4A, l-arabinose markedly upregulated the mRNA vention of l-arabinose for 12 weeks inhibited the mRNA expression of CYP7A1 compared with the HFHSD group, level of tumor necrosis factor alpha (TNF-α) and and sig- while no significant changes were observed in other key nificantly increased interferon-γ (IFN-γ), interleukin-1β enzymes for classical or alternative bile acid synthe- (IL-1β) mRNA levels compared to those of the HFHSD- sis pathways including CYP27A1, CYP7B1, and sterol fed group. No significant change in interleukin-6 (IL-6) 12α-hydroxylase (CYP8B1). Moreover, the protein levels mRNA level was observed between the control group of CYP7A1 and CYP27A1 were elevated in the liver from and l-arabinose group under the same assay condition. HFHSD-fed mice treated with l-arabinose (Fig. 4B, C). These results indicated that l-arabinose improved lipid Negative feedback regulation plays an important role in metabolism disorder and hepatic steatosis induced by bile acid synthesis [27, 28]. The alternation of key genes HFHSD. related to negative feedback of hepatic bile acid synthe- sis, including FXR, small heterodimer partner (SHP), as l A ‑ rabinose suppresses hepatic cholesterol synthesis well as HNF-4α were presented in Fig.  4D. The mRNA and facilitates reverse cholesterol transport and protein expressions of FXR were downregulated in Given that l-arabinose administration could alleviate mice treated with l-arabinose. As the target gene of FXR, the elevated serum lipid levels and hepatic lipid accu- SHP was shown to repress bile acid synthesis through mulation caused by HFHSD, we further investigated inhibition of HNF-4α [29]. Similarly, l-arabinose supple - whether l-arabinose suppresses hepatic lipids synthe - mentation also lowered mRNA expression of SHP follow- sis, especially hepatic cholesterol. The mRNA expres - ing FXR in the liver, leading to increased expression of sions of the key genes controlling cholesterol metabolism HNF-4α at both protein and mRNA levels (Fig. 4E, F). In in the liver were measured. As shown in Fig.  3A, the addition, bile salt export pump (BSEP) is responsible for mRNA levels of HMGCR and SREBP-1c significantly hepatic bile acids efflux into canaliculi [18]. The mRNA increased in HFHSD-fed mice, which mediate the key expression of BSEP was higher in the liver of l-arabinose- step in cholesterol and triglycerides synthesis. l-Arab - treated mice than that of the HFHSD group, which might inose treatment significantly downregulated the mRNA be in response to increased bile acid synthesis (Fig. 4E). expressions of HMGCR and SREBP-1c compared with the HFHSD group. However, l-arabinose treatment l A ‑ rabinose enhances the bile acids excretion and reduces slightly increased the mRNA expressions of liver X the intestinal bile acid reabsorption receptor (LXR) and sterol regulatory element-binding Based on the results above, l-arabinose treatment could protein-2 (SREBP2) expression but no significant dif - enhance the cholesterol uptake from the circulation and ference was found compared with the HFHSD group. conversion to bile acids, so we speculated that l-ara - Moreover, similar modulation of the protein expressions binose might affect the reabsorption and excretion of of HMGCR and SREBP-1c was observed in mice treated bile acids. Therefore, we first measured the content of with l-arabinose (Fig.  3B, C). In addition, the expression bile acids in the feces and urine of mice. The excretion alternation of genes related to reverse cholesterol trans- of bile acids both in the HFHSD and l-arabinose group port in the liver, including low-density lipoprotein recep- was significantly higher than that of the control group. tor (LDL-R), scavenger receptor class B type 1 (SR-B1), Notably, l-arabinose treatment remarkably increased ATP binding cassette transporter G1 (ABCG1), and ATP bile acid excretion in comparison with the HFHSD group binding cassette transporter A1 (ABCA1) were detected. (Fig.  5A). Meanwhile, l-arabinose intervention slightly The results showed that l-arabinose intervention increased the content of bile acids in urine (Fig.  5B). In W ang et al. Nutrition & Metabolism (2022) 19:30 Page 5 of 11 contrast to the HFHSD group, l-arabinose treatment significantly decreased the level of total serum bile acids (Fig.  5C). Besides that, the level of fecal cholesterol was no significant difference among the three groups (Fig. 5D). In addition, l-arabinose had apparent effects on the reabsorption of bile acids in the small intestine. Regula- tory factors involved in the reabsorption of bile acids, including ASBT, I-BABP, and FXR, were downregulated in mice given l-arabinose compared to the HFHSD and control group (Fig.  5E). Consistently, l-arabinose treat - ment also reduced the protein expressions of ASBT and Fig. 1 Eec ff ts of l -arabinose on body weight gain and index of liver and epididymal white adipose tissues. Body weight gain (A), FXR in the ileum (Fig.  5F, G). The mRNA expression of index of liver (B), and index of epididymal white adipose tissues (C) fibroblast growth factor 15 (FGF15), as an FXR target in HFHSD-fed mice after 12 weeks treatment of l -arabinose. Data gene in the intestine, was largely attenuated in mice fed are shown as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001. WAT l-arabinose. Besides, l-arabinose had no obvious effect white adipose tissues, Ctrl control group, HFHSD HFHSD-fed group, on cholesterol absorption in the ileum (Additional file  1: HFHSD + L-Ara HFHSD-fed group treated with l -arabinose Fig. S1A). These results revealed that l-arabinose could promote the excretion of fecal bile acids by suppressing the reabsorption of intestinal bile acids. in this study, indicating l-arabinose exerted cholesterol- lowering effects to some extent (Fig.  2). Furthermore, the Discussion accumulation of lipids in the liver caused by consum- Hypercholesterolemia and hypertriglyceridemia are the ing HFHSD can give rise to hepatic inflammation [26]. main hallmarks of CVD [1]. Dietary intervention of cho- Our observation of regulatory effects of l-arabinose on lesterol-lowering functional foods of natural origin has inflammatory cytokines, by lowering TNF-α and increas - attracted much research interest in CVD prevention and ing IFN-γ, IL-1β mRNA levels in the liver, suggested treatment [3]. Several lines of evidence suggested that that l-arabinose supplementation may improve hepatic l-arabinose is involved in the improvement of lipid meta - inflammation induced by HFHSD. Similar observations bolic disorder and immune regulation [5]. Whereas the on inhibitory effects of l-arabinose on TC and TG levels contributions of l-arabinose to cholesterol metabolism and inflammation in the liver have been reported before were yet to be sufficiently evaluated. In the present study, [9]. hypercholesterolemic mice induced by HFHSD were l-Arabinose supplementation was reported to regu - used to assess the effects of l-arabinose on cholesterol late glucose homeostasis via inhibition of hepatic gluco- metabolism based on the regulation of bile acid metabo- neogenesis and improvement of insulin sensitivity, thus lism, and the possible molecular mechanism underly- suppressing elevated plasma glucose and insulin levels ing its hypocholesterolemic activity was preliminarily in metabolic disorder mice [31]. Since insulin promotes explored. cholesterol synthesis, supplementation of l-arabinose It has been reported that l-arabinose prevents and may help disrupt endogenous cholesterol biosynthesis. improves lipid metabolic disorder in other diet-induced HMGCR catalyzes the rate-limiting step of cholesterol hypercholesterolemia, thereby might play a role in diet- synthesis, and downregulation of HMGCR at protein induced hyperlipidemia, atherosclerosis, and CVD [30]. and mRNA levels was observed, which might be related Consistent with previous animal studies [9], mice in the to a lower level of hepatic cholesterol in the l-arab - l-arabinose group showed reductions in body weight inose group (Fig.  3A, B). In addition, our previous work gain, index of liver and epididymal white adipose com- observed that protective effects of l-arabinose on abnor - pared to those of the HFHSD-fed group, which con- mal gluconeogenesis were associated with the activation tributed to the improvement of hypercholesterolemia of AMP-activated protein kinase (AMPK). l-Arabinose (Fig.  1). The beneficial effects of l-arabinose on improv - promoted the activation of AMPK and reduced acetyl- ing serum lipid profiles by effectively lowering serum TC CoA carboxylase (ACC) activity, which helps to inhibit and TG content in HFHSD-fed mice had been displayed fatty acid synthesis, subsequently leading to the reduc- in our previous study [31]. As an extension of our previ- tion of hepatic lipid accumulation in metabolic disorder ous study, l-arabinose administration also prevented the mice caused by HFHSD [31]. Moreover, animal studies increases in serum LDL-C, hepatic TC, and TG levels, also showed that l-arabinose could reduce lipid levels by accompanied by elevated serum HDL-C concentration Wang et al. Nutrition & Metabolism (2022) 19:30 Page 6 of 11 Fig. 2 Eec ff ts of l -arabinose on lipid levels in the serum and liver of HFHSD-fed mice treated with or without l -arabinose for 12 weeks. Serum HDL-C and LDL-C levels (A) and hepatic TC and TG levels (B). Representative H&E-stained images of liver sections (magnification, × 400) (C). The mRNA expression of hepatic key inflammatory markers, TNF-α, IFN-γ, IL-1β, and IL-6, determined by RT-qPCR analysis (D). The mRNA expression levels were ## normalized to 18S and were shown relative to mice in the control group. Data are shown as mean ± SEM. p < 0.01 compared with the control ### group; p < 0.001 compared with the control group; *p < 0.05 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara, HFHSD-fed group treated with l -arabinose Fig. 3 l -Arabinose modulates hepatic cholesterol synthesis and facilitates reverse cholesterol transport. Eec ff ts of l -arabinose on the relative expression of LXR, HMGCR, SREBP-1c, and SREBP2 measured by qRT-PCR analysis (A) in the liver of HFHSD-fed mice treated with or without l -arabinose for 12 weeks. Eec ff ts of l -arabinose on protein levels of SREBP-1c and HMGCR in the liver (B) with densitometric quantification (C). Expression of key genes in reverse cholesterol transport in the liver (D). The mRNA and protein expression levels were normalized to 18S and GAPDH respectively and were shown relative to mice in the control group. Data are shown as mean ± SEM. p < 0.05 compared with the control ## group; p < 0.01 compared with the control group; *p < 0.05 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara HFHSD-fed group treated with l -arabinose W ang et al. Nutrition & Metabolism (2022) 19:30 Page 7 of 11 Fig. 4 l -Arabinose promotes bile acid synthesis in the liver. The hepatic mRNA expressions of CYP7A1, CYP27A1, CYP7B1, and CYP8B1 (A) in HFHSD-fed mice treated with or without l -arabinose for 12 weeks. The protein levels of CYP7A1, CYP27A1, and CYP7B1 in the liver (B) with densitometric quantification (C). HSP90 was used as an internal reference. The hepatic mRNA expressions of FXR, SHP, HNF-4α, and BSEP (D). The protein expression of hepatic FXR and HNF-4α (E) with densitometric quantification (F).GAPDH was used as an internal reference. Data are shown # ## as mean ± SEM. p < 0.05 compared with the control group; p < 0.01 compared with the control group; *p < 0.05 compared with the HFHSD-fed group; **p < 0.01 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara HFHSD-fed group treated with l -arabinose acting as an inhibitor of liver lipogenic enzymes, such as transport, which facilitates the removal of excess cho- ACC, ATP citrate-lyase, and fatty acid synthase in rats lesterol from peripheral tissue back to the liver for fur- with high dietary sucrose [30]. Besides, Hao et  al. found ther metabolism. ABCG1 mainly mediates intracellular that l-arabinose dramatically ameliorated metabolic syn - cholesterol efflux to HDL, while ABCA1 promotes cho - drome by upregulating the genes participated in energy lesterol flow to apolipoprotein A1 [37]. Expressions of expenditure pyruvate dehydrogenase kinase 4 (PDK4) ABCG1 and ABCA1 were elevated in response to l-ara - and carnitine palmitoyltransferase 1α (CPT-1α) and binose intervention, which in line with the increase in downregulating adipogenesis genes ACC [8]. Our studies plasma HDL-C levels, therefore preventing excessive were also in line with these conclusions. cellular lipids accumulation (Fig.  3D). However, the reg- Concentrations of circulating cholesterol, including ulatory effects of l-arabinose on the reverse cholesterol LDL-C and HDL-C, were governed by reverse cholesterol transport process in peripheral tissue, especially in mac- transport, in which cholesterol from peripheral tissues is rophages, remain to be explored in our future research. transported to the liver for subsequent hepatic catabo- Our data revealed that the cholesterol-lowering effect of lism into bile and excretion [32, 33]. LDL-R and SR-B1 l-arabinose may be attributed in part to its role in sup - are two key receptors in this process [34]. LDL-R medi- pressing cholesterol synthesis and promoting reverse ates the removal of plasma LDL-C, whereas SR-B1, as cholesterol transport. the high-affinity receptor of HDL, is responsible for the Bile acid reabsorption and cholesterol absorption in selective uptake of HDL lipids [35, 36]. Upregulations of the small intestine are closely related to maintaining LDL-R and SR-B1 expression were observed after l-ara - cholesterol homeostasis, and lowering cholesterol func- binose treatment, which was associated with decreased tion of other substances is closely linked to these two plasma cholesterol level (Fig.  3D). Besides, ABCG1 and pathways [23, 38]. For instance, the underlying mecha- ABCA1 contribute to the process of reverse cholesterol nisms for the hypocholesterolemic activity of β-sitosterol Wang et al. Nutrition & Metabolism (2022) 19:30 Page 8 of 11 Fig. 5 l -Arabinose enhances the bile acids excretion and reduces intestinal bile acids reabsorption. Total bile acids content in the feces (A), urine (B) and serum (C), and fecal cholesterol level (D) in HFHSD-fed mice treated with or without l -arabinose for 12 weeks. The ileal mRNA expressions of ASBT, I-BABP, FXR, and FGF15 determined by qRT-PCR analysis (E). The ileal protein expressions of FXR, ASBT, and I-BABP determined by western # ## blotting (F) with densitometric quantification (G). Data are shown as mean ± SEM. p < 0.05 compared with the control group; p < 0.01 compared with the control group; *p < 0.05 compared with the HFHSD-fed group. Ctrl control group, HFHSD HFHSD-fed group, HFHSD + L-Ara HFHSD-fed group treated with l -arabinose laurate involve these two pathways mediated by reducing shown in Additional file  1: Fig. S1A, the less relevance of ASBT and I-BABP levels and downregulating intestinal cholesterol absorption to the hypocholesterolemic effects niemann-pick c1-like protein 1 (NPC1L1) respectively, of l-arabinose was observed as indicated by unchanged therefore, increasing the excretion of fecal bile acids and expression of related genes, which was consistent with cholesterol [39]. We next explored whether l-arabinose the results of fecal cholesterol content in the l-arabinose maintains cholesterol homeostasis by regulating bile group. Furthermore, previous studies have confirmed acid reabsorption and cholesterol absorption. Most bile that l-arabinose could protect the intestinal barrier from acids are reabsorbed into the intestinal epithelial cells by dextran sodium sulfate-induced colitis and gliadins- ASBT mainly localized at the enterocyte brush border, induced damage [6, 42]. In the present study, l-arabinose then transported to the basolateral membrane with the intervention could increase the mRNA expression of assistance of I-BABP, and finally, efflux into the portal tight junction proteins, mainly including ZO-1, occludin, blood and transport to the liver [40, 41]. Further research and claudin, which contributed to maintaining intestinal found that the inhibition of bile acid reabsorption by barrier integrity and epithelial barrier function (Addi- l-arabinose also occurred via depressing the expression tional file 1: Fig. S1B). of ASBT and I-BABP in the ileum, which was consistent As the major end product of cholesterol catabolism, with the results of increasing the fecal bile acids level and reabsorption of bile acid in the small intestine could lower serum bile acid content in the l-arabinose group influence the process of hepatic bile acid synthesis due (Fig.  5E, F). Besides, the expressions of key regulatory to enterohepatic circulation, consequently adjusting the factors related to cholesterol absorption and excretion in homeostasis of hepatic cholesterol [17]. As mentioned the ileum, including NPC1L1, microsomal triacylglycerol above, l-arabinose enhanced the excretion of fecal bile transport protein (MTP), ATP binding cassette transport- acids by reducing the bile acids reabsorption in the ileum, ers 5 and 8 (ABCG5 and ABCG8), acyl CoA cholesterol which might lead to hepatic cholesterol depletion. As acyltransferase 2 (ACAT2), were determined to explore expected, the impediment to enterohepatic circulation the effect of l-arabinose on cholesterol absorption. As of bile acids promoted hepatic bile acid synthesis in the W ang et al. Nutrition & Metabolism (2022) 19:30 Page 9 of 11 l-arabinose group, mainly through the CYP7A1 medi - FXR on hepatic bile acid synthesis was reserved by l-ara - ated classical pathway, to maintain the balance of the binose, whereas its exact mechanisms are still needed bile acids pool (Fig.  4A, B). Hepatic CYP7A1 expression to be investigated. Several studies identified inactivating was downregulated in insulin-resistant mice [43], and FXR-mediated negative feedback mechanism by which the increase in CYP7A1 expression is consistent with cholesterol-lowering functional foods accelerate bile acid our previous study showing that l-arabinose relieved synthesis [46, 47]. For instance, Geniposide enhanced hepatic insulin-resistant state induced by HFHSD or the hepatic synthesis of bile acids via FXR-mediated high sucrose diet (HSD). As a critical regulatory fac- negative feedback inhibition of bile acids, leading to the tor for bile acid synthesis and transport, FXR has a vital increase in cholesterol catabolism and reverse cholesterol influence on the enterohepatic circulation of bile acids, transport [24]. Consequently, it was speculated that the thus regulating the homeostasis of hepatic cholesterol cholesterol-lowering effect of l-arabinose was in part [44, 45]. l-Arabinose promoted bile acid synthesis in the ascribed to diminishing the reabsorption of intestinal bile present work, and we suspected that negative feedback acids, and then promoted the conversion of hepatic cho- regulation of bile acids mediated by FXR might be acti- lesterol into bile acids (Fig. 6). vated. However, as reflected by our results, the expres - sion of FXR in the ileum was decreased accompanied by Conclusions the lower level of fibroblast growth factor 15 (FGF15). In summary, we confirmed that hypercholester - Moreover, the expression of FXR and its target gene, olemia induced by HFHSD in mice could be ame- SHP, were also inhibited in the liver with a subsequent liorated by l -arabinose dietary intervention. The increase in expression of CYP7A1 at both mRNA and beneficial effects of l -arabinose on HFHSD-induced protein levels after l-arabinose treatment (Fig.  5E, F). hypercholesterolemia were associated with improved Our data supported that the negative regulatory effect of cholesterol homeostasis via the modulation of bile acid Fig. 6 Graphical abstract of the effects of l -arabinose on improving hypercholesterolemia in HFSD-fed mice. l -Arabinose not only inhibited cholesterol synthesis but also facilitated cholesterol transport from peripheral tissue to the liver, so as to reduce circulating cholesterol. Moreover, dietary administration with l -arabinose had beneficial effects on bile acids homeostasis by reducing the reabsorption of bile acids and promoting hepatic bile acid synthesis, thus accelerating the excretion of bile acids while enhancing the decomposition of cholesterol into bile acids, ultimately facilitating cholesterol homeostasis and alleviating hypercholesterolemia. Arrows (↑) represent upregulation of protein or mRNA expression. Arrows (↓) represent downregulation Wang et al. Nutrition & Metabolism (2022) 19:30 Page 10 of 11 Declarations metabolism. Our work provides insight into the devel- opment and application of functional foods containing Ethics approval and consent to participate l -arabinose against hypercholesterolemia, but the reg- All animal protocols and procedures were approved by the Laboratory Animal Ethics Committee of Jiangnan University (University JN. No20190315c0320630 ulatory mechanism needs to be further investigated. [26]). Consent for publication Abbreviations Not applicable. ABCA1: ATP binding cassette transporter A1; ABCG1: ATP binding cas- sette transporter G1; ASBT: Apical sodium-dependent bile salt transporter; Competing interest BSEP: Bile salt export pump; CVD: Cardiovascular diseases; CYP7A1: Cho- The authors declare that they have no competing interests. lesterol 7α-hydroxylase; CYP7B1: Oxysterol 7α-hydroxylase; CYP8B1: Sterol 12α-hydroxylase; CYP27A1: Mitochondrial sterol 27-hydroxylase; FXR: Author details Farnesoid X receptor; GAPDH: Glyceraldehyde-3-phosphate dehydroge- State Key Laboratory of Food Science and Technology, School of Food nase; HDL-C: High-density lipoprotein cholesterol; HMGCR : 3-Hydroxy- Science and Technology, Jiangnan University, Wuxi 214122, China. Col- 3-methylglutaryl-CoA reductase; HNF-4α: Hepatocyte nuclear factor-4α; lege of Cooking Science and Technology, Jiangsu College of Tourism, HFHSD: High-fat-high-sucrose diet; HSP90: Heat shock protein 90; I-BABP: Yangzhou 225000, China. China National Institute of Standardization, No. 4 Ileal-bile acid-binding protein; IFN-γ: Interferon-γ; IL-6: Interleukin-6; IL-1β: Zhichun Road, Haidian District, Beijing, China. Interleukin-1β; LDL-C: Low-density lipoprotein cholesterol; LDL-R: Low density lipoprotein receptor; LRH-1: Liver receptor homolog-1; LXR: Liver X receptor; Received: 25 January 2022 Accepted: 29 March 2022 SHP: Small heterodimer partner; SR-B1: Scavenger receptor class B type 1; SREBP-1c: Sterol regulatory element binding protein-1c; SREBP2: Sterol regula- tory element-binding protein-2; TC: Total cholesterol; TG: Triglyceride; TNF-α: Sumor necrosis factor-α. References Supplementary Information 1. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, et al. Heart disease The online version contains supplementary material available at https:// doi. and stroke statistics—2021 update. Circulation. 2021;143:e254–743. org/ 10. 1186/ s12986- 022- 00662-8. 2. Archundia Herrera MC, Subhan FB, Chan CB. Dietary Patterns and Car- diovascular Disease Risk in People with Type 2 Diabetes. Curr Obes Rep. 2017;6:405–13. Additional file 1. Table S1: Primer Sequences. Fig. S1: Relative mRNA 3. Chen Z-Y, Jiao R, Ma KY. Cholesterol-lowering nutraceuticals and func- expression of genes involved in cholesterol metabolism in the small intes- tional foods. J Agric Food Chem. 2008;56:8761–73. tine of HFHSD-fed mice treated with or without L-arabinose for 12 weeks 4. Ouimet M, Barrett TJ, Fisher EA. HDL and reverse cholesterol transport. (A). The mRNA expression levels of ZO-1, occludin, and claudin in ileum Circ Res. 2019;124:1505–18. sections (B). Data are shown as mean ± SEM. p < 0.05 compared with the ## ### 5. Fehér C. Novel approaches for biotechnological production and applica- control group; p < 0.01 compared with the control group; p < 0.001 tion of l -arabinose. J Carbohydr Chem. 2018;37:251–84. compared with the control group; *p < 0.05 compared with the HFHSD- 6. Li Y, Pan H, Liu J-x, Li T, Liu S, Shi W, Sun C, Fan M, Xue L, Wang Y, et al. fed group. Ctrl: control group; HFHSD: HFHSD-fed group; HFHSD+L-Ara: l -Arabinose inhibits colitis by modulating gut microbiota in mice. J Agric HFHSD-fed group treated with L-arabinose. Fig. S2: Serum FFA level Food Chem. 2019;67:13299–306. in HFHSD-fed mice treated with or without L-arabinose for 12 weeks. 7. Krog-Mikkelsen I, Hels O, Tetens I, Holst JJ, Andersen JR, Bukhave K. The **p < 0.01 compared with the HFHSD-fed group. Ctrl: control group; effects of l -arabinose on intestinal sucrase activity: dose-response studies HFHSD: HFHSD-fed group; HFHSD+L-Ara: HFHSD-fed group treated with in vitro and in humans. Am J Clin Nutr. 2011;94:472–8. L-arabinose. 8. Hao L, Lu X, Sun M, Li K, Shen L, Wu T. Protective effects of l -arabinose in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. Acknowledgements Food Nutr Res. 2015;59:28886. None. 9. Zhao L, Wang Y, Zhang G, Zhang T, Lou J, Liu J. l -Arabinose elicits gut- derived hydrogen production and ameliorates metabolic syndrome in Author contributions C57BL/6J mice on high-fat-diet. Nutrients. 2019;11:3054. YW and YL designed the study. YW, JJZ, QL, JXL, YJS, and KLZ conducted the 10. Shibanuma K, Degawa Y, Houda K. Determination of the transient period research and analyzed the data. YW and YL wrote the initial paper. MCF, HFQ, of the EIS complex and investigation of the suppression of blood glucose and LW revised the paper. LW provided research funding. All authors read and levels by l -arabinose in healthy adults. Eur J Nutr. 2011;50:447–53. approved the final manuscript. 11. Seri K, Sanai K, Matsuo N, Kawakubo K, Xue C, Inoue S. l-Arabinose selectively inhibits intestinal sucrase in an uncompetitive manner Funding and suppresses glycemic response after sucrose ingestion in animals. This work was supported by the National Natural Science Foundation of Metabolism. 1996;45:1368–74. China (31900841, 32071166), the Young Eliet Scientists Sponsorship Program 12. Luo J, Yang H, Song B-L. Mechanisms and regulation of cholesterol by CAST (2020QNRC001), the Research and Development Program of homeostasis. Nat Rev Mol Cell Biol. 2020;21:225–45. Wuxi (N20203005), the Research and Development Program of Tianchang 13. Chang T-Y, Chang CCY, Ohgami N, Yamauchi Y. Cholesterol sensing, traf- ( TZY202002), the "Qing Lan Project" of Jiangsu Province, the Open Project ficking, and esterification. Annu Rev Cell Dev Biol. 2006;22:129–57. Program of China-Canada Joint Lab of Food Nutrition and Health, Beijing Tech- 14. Yu X-H, Zhang D-W, Zheng X-L, Tang C-K. Cholesterol transport system: nology and Business University (BTBU), and the Fundamental Research Funds an integrated cholesterol transport model involved in atherosclerosis. for the Central Universities (JUSRP221001). Prog Lipid Res. 2019;73:65–91. 15. Gil-Ramirez A, Caz V, Smiderle FR, Martin-Hernandez R, Largo C, Tab- Availability of data and materials ernero M, Marin FR, Iacomini M, Reglero G, Soler-Rivas C. Water-soluble The datasets underlying this article are available from the corresponding compounds from lentinula edodes influencing the HMG-CoA reductase author on reasonable request. W ang et al. Nutrition & Metabolism (2022) 19:30 Page 11 of 11 activity and the expression of genes involved in the cholesterol metabo- metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet. Food lism. J Agric Food Chem. 2016;64:1910–20. Nutr Res. 2019;63:66. 16. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. 39. Chen S, Wang R, Cheng M, Wei G, Du Y, Fan Y, Li J, Li H, Deng Z. Serum Annu Rev Biochem. 2003;72:137–74. cholesterol-lowering activity of beta-sitosterol laurate is attributed to the 17. van de Peppel IP, Verkade HJ, Jonker JW: Metabolic consequences of ileal reduction of both cholesterol absorption and bile acids reabsorption in interruption of the enterohepatic circulation of bile acids. Am J Physiol hamsters. J Agric Food Chem. 2020;68:10003–14. Gastrointest Liver Physiol. 2020;319:G619-25. 40. Li M, Wang Q, Li Y, Cao S, Zhang Y, Wang Z, Liu G, Li J, Gu B. Apical sodium- 18. de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids dependent bile acid transporter, drug target for bile acid related diseases in metabolism. Cell Metab. 2013;17:657–69. and delivery target for prodrugs: current and future challenges. Pharma- 19. Neimark E, Chen F, Li X, Shneider BL. Bile acid–induced negative feed- col Therap. 2020;212:107539. back regulation of the human ileal bile acid transporter. Hepatology. 41. Badiee M, Tochtrop GP. Bile acid recognition by mouse ileal bile acid bind- 2004;40:149–56. ing protein. ACS Chem Biol. 2017;12(12):3049–56. 20. Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal absorption 42. Wang Y, Sun J, Xue L, Liu J, Nie C, Fan M, Qian H, Zhang D, Ying H, Li Y, of bile acids in health and disease. Compr Physiol. 2019;10:21–56. Wang L. l-Arabinose attenuates gliadin-induced food allergy via regula- 21. Li-Hawkins J, Gåfvels M, Olin M, Lund EG, Andersson U, Schuster G, tion of Th1/Th2 balance and upregulation of regulatory T cells in mice. J Björkhem I, Russell DW, Eggertsen G. Cholic acid mediates nega- Agric Food Chem. 2021;69:3638–46. tive feedback regulation of bile acid synthesis in mice. J Clin Investig. 43. Kim H, Bartley GE, Rimando AM, Yokoyama W. Hepatic gene expression 2002;110:1191–200. related to lower plasma cholesterol in hamsters fed high-fat diets sup- 22. Yang Y, Sun Q, Xu X, Yang X, Gao Y, Sun X, Zhao Y, Ding Z, Ge W, Cheng plemented with blueberry peels and peel extract. J Agric Food Chem. R, Zhang J. Oral administration of succinoglycan riclin improves 2010;58:3984–91. diet-induced hypercholesterolemia in mice. J Agric Food Chem. 44. Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. 2019;67:13307–17. Mol Cell Endocrinol. 2013;368:17–29. 23. Li D, Cui Y, Wang X, Liu F, Li X. Apple polyphenol extract improves high-fat 45. Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of diet-induced hepatic steatosis by regulating bile acid synthesis and gut metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, microbiota in C57BL/6 male mice. J Agric Food Chem. 2021;69:6829–41. and nonalcoholic fatty liver disease. Gastroenterology. 2017;152:1679- 24. Liu J, Li Y, Sun C, Liu S, Yan Y, Pan H, Fan M, Xue L, Nie C, Zhang H, et al. 1694.e1673. Geniposide reduces cholesterol accumulation and increases its excretion 46. Zeng BB, Zhang LY, Chen C, Zhang TT, Xue CH, Yanagita T, Li ZJ, Wang YM. by regulating the FXR-mediated liver-gut crosstalk of bile acids. Pharma- Sea cucumber sterol alleviates the lipid accumulation in high-fat-fructose col Res. 2020;152:104631. diet fed mice. J Agric Food Chem. 2020;68:9707–17. 25. Liu J, Nie C, Xue L, Yan Y, Liu S, Sun J, Fan M, Qian H, Ying H, Wang L, Li Y. 47. Duan R, Guan X, Huang K, Zhang Y, Li S, Xia J, Shen M. Flavonoids from Growth hormone receptor disrupts glucose homeostasis via promoting whole-grain oat alleviated high-fat diet-induced hyperlipidemia via and stabilizing retinol binding protein 4. Theranostics. 2021;11:8283–300. regulating bile acid metabolism and gut microbiota in mice. J Agric Food 26. Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: Chem. 2021;69:7629–40. emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48:677–85. 27. Kong B, Wang L, Chiang JY, Zhang Y, Klaassen CD, Guo GL. Mechanism Publisher’s Note of tissue-specific farnesoid X receptor in suppressing the expression of Springer Nature remains neutral with regard to jurisdictional claims in pub- genes in bile-acid synthesis in mice. Hepatology. 2012;56:1034–43. lished maps and institutional affiliations. 28. Chiang JYL. Negative feedback regulation of bile acid metabolism: impact on liver metabolism and diseases. Hepatology. 2015;62:1315–7. 29. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000;6:517–26. 30. Osaki S, Kimura T, Sugimoto T, Hizukuri S, Iritani N. l -Arabinose feeding prevents increases due to dietary sucrose in lipogenic enzymes and triacylglycerol levels in rats. J Nutr. 2001;131:796–9. 31. Wang Y, Guan Y, Xue L, Liu J, Yang Z, Nie C, Yan Y, Liu S, Sun J, Fan M, et al. l-Arabinose suppresses gluconeogenesis through modulating AMP-activated protein kinase in metabolic disorder mice. Food Funct. 2021;12:1745–56. 32. Frambach SJCM, de Haas R, Smeitink JAM, Rongen GA, Russel FGM, Schir- ris TJJ. Brothers in arms: ABCA1- and ABCG1-mediated cholesterol efflux as promising targets in cardiovascular disease treatment. Pharmacol Rev. 2020;72:152. 33. Kennedy MA, Barrera GC, Nakamura K, Baldán Á, Tarr P, Fishbein MC, Frank J, Francone OL, Edwards PA. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : Metab. 2005;1:121–31. 34. Strickland DK, Gonias SL, Argraves WS. Diverse roles for the LDL receptor fast, convenient online submission family. Trends Endocrinol Metab. 2002;13:66–74. thorough peer review by experienced researchers in your field 35. Shen W-J, Azhar S, Kraemer FB. SR-B1: a unique multifunctional receptor for cholesterol influx and efflux. Annu Rev Physiol. 2018;80:95–116. rapid publication on acceptance 36. Linton MF, Tao H, Linton EF, Yancey PG. SR-BI: a multifunctional receptor support for research data, including large and complex data types in cholesterol homeostasis and atherosclerosis. Trends Endocrinol Metab. • gold Open Access which fosters wider collaboration and increased citations 2017;28:461–72. 37. Dan L, Bart Z, Ying M, Illiana V, Berkel T. ATP-binding cassette transport- maximum visibility for your research: over 100M website views per year ers A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis. Curr Drug Targets. At BMC, research is always in progress. 2011;12:647–60. Learn more biomedcentral.com/submissions 38. Han S, Zhang W, Zhang R, Jiao J, Fu C, Tong X, Zhang W, Qin L. Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol

Journal

Nutrition & MetabolismSpringer Journals

Published: Apr 15, 2022

Keywords: l-Arabinose; Cholesterol metabolism; Bile acid; Hypercholesterolemia

There are no references for this article.