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Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha.

Authors
  • Lehrke, Michael
  • Lebherz, Corinna
  • Millington, Segan C
  • Guan, Hong-Ping
  • Millar, John
  • Rader, Daniel J
  • Wilson, James M
  • Lazar, Mitchell A
Type
Published Article
Journal
Cell Metabolism
Publisher
Elsevier
Publication Date
May 01, 2005
Volume
1
Issue
5
Pages
297–308
Identifiers
PMID: 16054077
Source
Medline
License
Unknown

Abstract

The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXRalpha in the links between diet, serum lipids, and atherosclerosis. A modest increase in hepatic LXRalpha worsened serum lipid profiles in LDL-receptor null mice fed normal chow but had the opposite effect on lipids and afforded strong protection against atherosclerosis on a Western diet. The beneficial effect of hepatic LXRalpha was abrogated by a synthetic LXR agonist, which activated SREBP-1c and its target genes. Thus, the interplay between diet and hepatic LXRalpha is a critical determinant of serum lipid profiles and cardiovascular risk, and selective modulation of LXR target genes in liver can ameliorate hyperlipidemia and cardiovascular disease.

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