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
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anticholesteremic Agents / pharmacology
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Arteriosclerosis / metabolism
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CCAAT-Enhancer-Binding Proteins / drug effects
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cardiovascular Diseases / metabolism*
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Diet*
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Female
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Gene Expression Regulation
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Humans
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Hydrocarbons, Fluorinated
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Lipid Metabolism*
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Lipids / blood
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Liver / metabolism*
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Liver X Receptors
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Orphan Nuclear Receptors
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Sterol Regulatory Element Binding Protein 1
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Sulfonamides
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Anticholesteremic Agents
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CCAAT-Enhancer-Binding Proteins
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DNA-Binding Proteins
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Hydrocarbons, Fluorinated
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Lipids
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Liver X Receptors
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NR1H3 protein, human
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Nr1h3 protein, mouse
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Orphan Nuclear Receptors
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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SREBF1 protein, human
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Srebf1 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Sulfonamides
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T0901317
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Transcription Factors