Abstract
The liver X receptors (LXRs) sense oxysterols and regulate genes involved in cholesterol metabolism. Synthetic agonists of LXRs are potent stimulators of fatty acid synthesis, which is mediated largely by sterol regulatory element-binding protein-1c (SREBP-1c). Paradoxically, an improved hepatic lipid profile by LXR was observed in mice fed a Western high fat (HF) diet. To explore the underlying mechanism, we administered mice normal chow or an HF diet and overexpressed LXRalpha in the liver. The HF diet with tail-vein injection of adenovirus of LXRalpha increased the expression of LXR-targeted genes involved in cholesterol reverse transport but not those involved in fatty acid synthesis. A similar effect was also observed with the use of 22R-hydroxycholesterol, an LXR ligand, in cultured hepatocytes. Consequently, SREBP-1c maturation was inhibited by the HF diet, which resulted from the induction of Insig-2a. Importantly, increased cholesterol level suppressed the expression of 2,3-oxidosqualene cyclase (OSC), which led to an increase in endogenous LXR ligand(s). Furthermore, siRNA-mediated knockdown of OSC expression enhanced LXR activity and selectively up-regulated LXR-targeted genes involved in cholesterol reverse transport. Thus, down-regulation of OSC may account for a novel mechanism underlying the LXR-mediated lipid metabolism in the liver of mice fed an HF diet.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae
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Animals
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Cell Line, Tumor
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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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Dietary Fats / pharmacology*
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / physiology*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Intramolecular Transferases / biosynthesis*
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Intramolecular Transferases / genetics
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Lipid Metabolism / drug effects
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Lipid Metabolism / physiology*
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Liver / enzymology*
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Liver X Receptors
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Orphan Nuclear Receptors
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Rats
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Rats, Sprague-Dawley
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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 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
Substances
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DNA-Binding Proteins
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Dietary Fats
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INSIG2 protein, human
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Insig2 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Liver X Receptors
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Membrane Proteins
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NR1H3 protein, human
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Nr1h3 protein, mouse
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Nr1h3 protein, rat
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Orphan Nuclear Receptors
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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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Intramolecular Transferases
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lanosterol synthase