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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 4; pp. 781 - 786
• Main Authors: Yasuda, Tomoyuki, Grillot, Didier, Billheimer, Jeffery T, Briand, François, Delerive, Philippe, Huet, Stephane, Rader, Daniel J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.04.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Benzoates - pharmacology; Benzylamines - pharmacology; Biological and medical sciences; Biological Transport; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Line; Cholesterol - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Feces - chemistry; Intestine, Small - drug effects; Intestine, Small - metabolism; Liver - drug effects; Liver - metabolism; Liver X Receptors; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - genetics; Orphan Nuclear Receptors - metabolism; Time Factors; high density lipoproteins; reverse cholesterol transport; Digestive system; Liver; Lipids; Cardiovascular disease; Lipoprotein; Cholesterol; Vascular disease; tissue specific; Atherosclerosis; Transport; liver X receptor; Macrophage
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.109.195693

OBJECTIVE—We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-cholesterol 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 LXRα/β vs wild-type macrophages. Whereas GW3965 treatment promoted fecal excretion compared with vehicle, its overall ability to promote mRCT was significantly attenuated using LXRα/β knockout macrophages. CONCLUSION—We demonstrate that intestinal-specific LXR agonism promotes macrophage RCT in vivo and that macrophage LXR itself plays an important, but not predominant, role in promoting RCT in response to an LXR agonist.