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Tissue-Specific Liver X Receptor Activation Promotes Macrophage Reverse Cholesterol Transport In Vivo

Tissue-Specific Liver X Receptor Activation Promotes Macrophage Reverse Cholesterol Transport In... Tissue-Specific Liver X Receptor Activation Promotes Macrophage Reverse Cholesterol Transport In Vivo Tomoyuki Yasuda, Didier Grillot, Jeffery T. Billheimer, Franc¸ois Briand, Philippe Delerive, Stephane Huet, Daniel J. Rader Objective—We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-cho- lesterol transport (mRCT) in vivo. Because LXR are expressed in multiple tissues involved in RCT (macrophages, liver, intestine), we analyzed the effect of tissue-specific LXR agonism on mRCT. Methods and Results—In initial studies, the systemic LXR agonist GW3965 failed to promote mRCT in a setting in which LXR was expressed in macrophages but not in liver or intestine. To evaluate the effect of LXR activation specifically in small intestine on mRCT, wild-type mice were treated with either intestinal-specific LXR agonist (GW6340) or systemic LXR agonist (GW3965). Both GW3965 and GW6340 significantly promoted excretion of [ H]-sterol in feces by 162% and 52%, respectively. To evaluate the requirement for macrophage LXR activation, we assessed the ability of GW3965 to promote mRCT in wild-type mice using primary macrophages deficient in LXR/ vs wild-type macrophages. Whereas GW3965 treatment promoted fecal excretion compared with vehicle, its overall ability to promote mRCT was significantly attenuated using LXR/ knockout macrophages. Conclusion—We demonstrate that http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arteriosclerosis, Thrombosis, and Vascular Biology Wolters Kluwer Health

Tissue-Specific Liver X Receptor Activation Promotes Macrophage Reverse Cholesterol Transport In Vivo

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ISSN
1079-5642
eISSN
1524-4636
DOI
10.1161/ATVBAHA.109.195693
pmid
20110577

Abstract

Tissue-Specific Liver X Receptor Activation Promotes Macrophage Reverse Cholesterol Transport In Vivo Tomoyuki Yasuda, Didier Grillot, Jeffery T. Billheimer, Franc¸ois Briand, Philippe Delerive, Stephane Huet, Daniel J. Rader Objective—We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-cho- lesterol transport (mRCT) in vivo. Because LXR are expressed in multiple tissues involved in RCT (macrophages, liver, intestine), we analyzed the effect of tissue-specific LXR agonism on mRCT. Methods and Results—In initial studies, the systemic LXR agonist GW3965 failed to promote mRCT in a setting in which LXR was expressed in macrophages but not in liver or intestine. To evaluate the effect of LXR activation specifically in small intestine on mRCT, wild-type mice were treated with either intestinal-specific LXR agonist (GW6340) or systemic LXR agonist (GW3965). Both GW3965 and GW6340 significantly promoted excretion of [ H]-sterol in feces by 162% and 52%, respectively. To evaluate the requirement for macrophage LXR activation, we assessed the ability of GW3965 to promote mRCT in wild-type mice using primary macrophages deficient in LXR/ vs wild-type macrophages. Whereas GW3965 treatment promoted fecal excretion compared with vehicle, its overall ability to promote mRCT was significantly attenuated using LXR/ knockout macrophages. Conclusion—We demonstrate that

Journal

Arteriosclerosis, Thrombosis, and Vascular BiologyWolters Kluwer Health

Published: Apr 1, 2010

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