Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha.
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.
Lehrke
Michael
M
Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Lebherz
Corinna
C
Millington
Segan C
SC
Guan
Hong-Ping
HP
Millar
John
J
Rader
Daniel J
DJ
Wilson
James M
JM
Lazar
Mitchell A
MA
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001161:Arteriosclerosis / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014157:Transcription Factors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides