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Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice
Yuan Zhang, … , David J. Mangelsdorf, Ira G. Schulman
Yuan Zhang, … , David J. Mangelsdorf, Ira G. Schulman
Published April 9, 2012
Citation Information: J Clin Invest. 2012;122(5):1688-1699. https://doi.org/10.1172/JCI59817.
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Research Article Hepatology

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

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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

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

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Figure 5

LXR agonists increase HDL cholesterol in the absence of hepatic LXRα.

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LXR agonists increase HDL cholesterol in the absence of hepatic LXRα.
Fl...
Floxed and LivKO female mice 4–6 months of age (n = 5–6) were fed a chow diet containing vehicle or T0901317 (40 mpk) for 8 days. (A) Plasma total cholesterol and (B) hepatic cholesterol were determined as described in Methods. Plasma from floxed (C) and LivKO (D) mice treated with or without T0901317 was pooled and subjected to FPLC for lipoprotein analysis. Cholesterol content of each fraction was assayed enzymatically. Gene expression from liver (E) and small intestine (F) harvested at completion of the experiment was assayed by quantitative real-time PCR. Data are mean ± SEM. *P ≤ 0.05 between vehicle- and T0901317-treated animals of the same genotype; †P ≤ 0.05 between floxed and LivKO mice with the same treatment.

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