Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice

Yuan Zhang, Sarah R. Breevoort, Jerry Angdisen, Mingui Fu, Daniel R. Schmidt, Sam R. Holmstrom, Steven A. Kliewer, David J. Mangelsdorf, Ira G. Schulman

Research output: Contribution to journalArticle

108 Scopus citations

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, liverspecific 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.

Original languageEnglish (US)
Pages (from-to)1688-1699
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number5
DOIs
StatePublished - May 1 2012

ASJC Scopus subject areas

  • Medicine(all)

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