Abstract
Cholesterol 7alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of hepatic bile acid biosynthesis from cholesterol. During fasting and in type I diabetes, elevated levels of peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) induce expression of the Cyp7A1 gene and overexpression of PGC-1alpha in hepatoma cells stimulates bile acid synthesis. Using Ad-PGC-1alpha-RNA interference to induce acute disruption of PGC-1alpha in mice, here we show that PGC-1alpha is necessary for fasting-mediated induction of CYP7A1. Co-immunoprecipitation and promoter activation studies reveal that the induction of CYP7A1 is mediated by direct interaction between PGC-1alpha and the AF2 domain of liver receptor homolog-1 (LRH-1). In contrast, the very similar PGC-1beta could not substitute for PGC-1alpha. We also show that transactivation of PGC-1alpha and LRH-1 is repressed by the small heterodimer partner (SHP). Treatment of mice with GW4064, a synthetic agonist for farnesoid X receptor, induced SHP expression and decreased both the recruitment of PGC-1alpha to the Cyp7A1 promoter and the fasting-induced expression of CYP7A1 mRNA. These data suggest that PGC-1alpha is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1alpha to inhibit CYP7A1 expression. Overall, these studies provide further evidence for the important role of PGC-1alpha in bile acid homeostasis and suggest that pharmacological targeting of farnesoid X receptor in vivo can be used to reverse the increase in CYP7A1 associated with adverse metabolic conditions.
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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Animals
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Bile Acids and Salts / biosynthesis
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Bile Acids and Salts / genetics
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cholesterol / genetics
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Cholesterol / metabolism
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Cholesterol 7-alpha-Hydroxylase / biosynthesis*
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Cholesterol 7-alpha-Hydroxylase / genetics
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Diabetes Mellitus, Type 1 / enzymology*
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Diabetes Mellitus, Type 1 / genetics
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Enzyme Induction / drug effects
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Enzyme Induction / genetics
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Fasting / metabolism*
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Homeostasis / drug effects
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Homeostasis / genetics
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Humans
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Isoxazoles / pharmacology
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Liver / enzymology*
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Male
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Mice
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Promoter Regions, Genetic / genetics
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Protein Structure, Tertiary
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RNA Interference
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RNA-Binding Proteins
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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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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / agonists
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation / drug effects
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Transcriptional Activation / genetics
Substances
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Bile Acids and Salts
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Carrier Proteins
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DNA-Binding Proteins
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Heat-Shock Proteins
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Isoxazoles
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NR5A2 protein, human
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Nr5a2 protein, mouse
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PPARGC1A protein, human
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PPARGC1B protein, human
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA-Binding Proteins
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Receptors, Cytoplasmic and Nuclear
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Trans-Activators
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Transcription Factors
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nuclear receptor subfamily 0, group B, member 2
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farnesoid X-activated receptor
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Cholesterol
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Cholesterol 7-alpha-Hydroxylase
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Cyp7a1 protein, mouse
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GW 4064