Abstract
The current paper describes a line of cultured rat hepatoma cells (McA-RH7777 cells) that mimics the behavior of rat liver by producing an excess of mRNA for sterol regulatory element-binding protein 1c (SREBP-1c) as opposed to SREBP-1a. These two transcripts are derived from a single gene by use of alternative promoters that are separated by many kilobases in the genome. The high level of SREBP-1c mRNA is abolished when cholesterol synthesis is blocked by compactin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase that inhibits cholesterol synthesis. Levels of SREBP-1c mRNA are restored by mevalonate, the product of the HMG CoA reductase reaction, and by ligands for the nuclear hormone receptor LXR, including 22(R)-hydroxycholesterol and T0901317. These data suggest that transcription of the SREBP-1c gene in hepatocytes requires tonic activation of LXR by an oxysterol intermediate in the cholesterol biosynthetic pathway. Reduction of this intermediate lowers SREBP-1c levels, and this in turn is predicted to lower the rates of fatty acid biosynthesis in liver.
Publication types
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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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CCAAT-Enhancer-Binding Proteins / genetics*
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CCAAT-Enhancer-Binding Proteins / metabolism
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Carcinoma, Hepatocellular
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Cholesterol / metabolism
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Cholesterol / pharmacology
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Gene Expression
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Humans
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Hydroxycholesterols / metabolism
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Hydroxycholesterols / pharmacology
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Ligands
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Liver X Receptors
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Lovastatin / analogs & derivatives*
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Lovastatin / pharmacology
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Orphan Nuclear Receptors
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RNA, Messenger*
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Transcription Factors / genetics
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Tumor Cells, Cultured
Substances
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CCAAT-Enhancer-Binding Proteins
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DNA-Binding Proteins
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Hydroxycholesterols
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Ligands
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Liver X Receptors
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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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SREBF2 protein, human
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Transcription Factors
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22-hydroxycholesterol
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mevastatin
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25-hydroxycholesterol
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Cholesterol
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Lovastatin