Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha

Cell Metab. 2005 May;1(5):297-308. doi: 10.1016/j.cmet.2005.04.005.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology
  • Arteriosclerosis / metabolism
  • CCAAT-Enhancer-Binding Proteins / drug effects
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cardiovascular Diseases / metabolism*
  • DNA-Binding Proteins / agonists
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diet*
  • Female
  • Gene Expression Regulation
  • Humans
  • Hydrocarbons, Fluorinated
  • Lipid Metabolism*
  • Lipids / blood
  • Liver / metabolism*
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Orphan Nuclear Receptors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Anticholesteremic Agents
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Lipids
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • TO-901317
  • Transcription Factors