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Mol Pharmacol. 2018 Oct;94(4):1145-1154. doi: 10.1124/mol.118.112672. Epub 2018 Jul 25.

Chronic Activation of Liver X Receptor Sensitizes Mice to High Cholesterol Diet-Induced Gut Toxicity.

Author information

1
Center for Pharmacogenetics and Department of Pharmaceutical Sciences (W.G.G., H.U., J.Y., M.X., S.R., W.X.), Departments of Cell Biology and Physiology (D.B.S.) and Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Institute of Clinical Pharmacology and Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, China (M.H.).
2
Center for Pharmacogenetics and Department of Pharmaceutical Sciences (W.G.G., H.U., J.Y., M.X., S.R., W.X.), Departments of Cell Biology and Physiology (D.B.S.) and Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Institute of Clinical Pharmacology and Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, China (M.H.) wex6@pitt.edu.

Abstract

Cholesterol is essential for numerous biologic functions and processes, but an excess of intracellular cholesterol can be toxic. Intestinal cholesterol absorption is a major determinant of plasma cholesterol level. The liver X receptor (LXR) is a nuclear receptor known for its activity in cholesterol efflux and reverse cholesterol transport. In this study, we uncovered a surprising function of LXR in intestinal cholesterol absorption and toxicity. Genetic or pharmacologic activation of LXRα-sensitized mice to a high-cholesterol diet (HCD) induced intestinal toxicity and tissue damage, including the disruption of enterocyte tight junctions, whereas the same HCD caused little toxicity in the absence of LXR activation. The gut toxicity in HCD-fed LXR-KI mice may have been accounted for by the increased intestinal cholesterol absorption and elevation of enterocyte and systemic levels of free cholesterol. The increased intestinal cholesterol absorption preceded the gut toxicity, suggesting that the increased absorption was not secondary to tissue damage. The heightened sensitivity to HCD in the HCD-fed LXRα-activated mice appeared to be intestine-specific because the liver was not affected despite activation of the same receptor in this tissue. Moreover, heightened sensitivity to HCD cannot be reversed by ezetimibe, a Niemann-Pick C1-like 1 inhibitor that inhibits intestinal cholesterol absorption, suggesting that the increased cholesterol absorption in LXR-activated intestine is mediated by a mechanism that has yet to be defined.

PMID:
30045953
PMCID:
PMC6108576
[Available on 2019-10-01]
DOI:
10.1124/mol.118.112672

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