t0901317 and Cardiovascular-Diseases

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.

Topics: Animals; Anticholesteremic Agents; Arteriosclerosis; Cardiovascular Diseases; CCAAT-Enhancer-Binding Proteins; Diet; DNA-Binding Proteins; Female; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Lipid Metabolism; Lipids; Liver; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Sulfonamides; Transcription Factors