title: Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice.
abstract: Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRα in hepatocytes. Liver-specific deletion of LXRα in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRα for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRα increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRα, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRα eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Breevoort
authors.forename: Jerry
authors.initials: J
authors.lastname: Angdisen
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schmidt
authors.forename: Sam R
authors.initials: SR
authors.lastname: Holmstrom
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D055786:Gene Knockout Techniques; D006706:Homeostasis; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000627:therapeutic use; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010316:Particle Size; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D014280:Triglycerides; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides