Functional interaction of hepatic nuclear factor-4 and peroxisome proliferator-activated receptor-gamma coactivator 1alpha in CYP7A1 regulation is inhibited by a key lipogenic activator, sterol regulatory element-binding protein-1c.
Insulin inhibits transcription of cholesterol 7alpha-hydroxylase (Cyp7a1), a key gene in bile acid synthesis, and the hepatic nuclear factor-4 (HNF-4) site in the promoter was identified as a negative insulin response sequence. Using a fasting/feeding protocol in mice and insulin treatment in HepG2 cells, we explored the inhibition mechanisms. Expression ... of sterol regulatory element-binding protein-1c (SREBP-1c), an insulin-induced lipogenic factor, inversely correlated with Cyp7a1 expression in mouse liver. Interaction of HNF-4 with its coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), was observed in livers of fasted mice and was reduced after feeding. Conversely, HNF-4 interaction with SREBP-1c was increased after feeding. In vitro studies suggested that SREBP-1c competed with PGC-1alpha for direct interaction with the AF2 domain of HNF-4. Reporter assays showed that SREBP-1c, but not of a SREBP-1c mutant lacking the HNF-4 interacting domain, inhibited HNF-4/PGC-1alpha transactivation of Cyp7a1. SREBP-1c also inhibited PGC-1alpha-coactivation of estrogen receptor, constitutive androstane receptor, pregnane X receptor, and farnesoid X receptor, implying inhibition of HNF-4 by SREBP-1c could extend to other nuclear receptors. In chromatin immunoprecipitation studies, HNF-4 binding to the promoter was not altered, but PGC-1alpha was dissociated, SREBP-1c and histone deacetylase-2 (HDAC2) were recruited, and acetylation of histone H3 was decreased upon feeding. Adenovirus-mediated expression of a SREBP-1c dominant-negative mutant, which blocks the interaction of SREBP-1c and HNF-4, partially but significantly reversed the inhibition of Cyp7a1 after feeding. Our data show that SREBP-1c functions as a non-DNA-binding inhibitor and mediates, in part, suppression of Cyp7a1 by blocking functional interaction of HNF-4 and PGC-1alpha. This mechanism may be relevant to known repression of many other HNF-4 target genes upon feeding.
Mesh Terms:
Animals, COS Cells, Cell Line, Cercopithecus aethiops, Cholesterol 7-alpha-Hydroxylase, DNA-Binding Proteins, Gene Expression Regulation, Hepatocyte Nuclear Factor 4, Humans, Insulin, Liver, Mice, PPAR gamma, Receptors, Cytoplasmic and Nuclear, Receptors, Estrogen, Sterol Regulatory Element Binding Protein 1, Transcription Factors, Transcriptional Activation
Animals, COS Cells, Cell Line, Cercopithecus aethiops, Cholesterol 7-alpha-Hydroxylase, DNA-Binding Proteins, Gene Expression Regulation, Hepatocyte Nuclear Factor 4, Humans, Insulin, Liver, Mice, PPAR gamma, Receptors, Cytoplasmic and Nuclear, Receptors, Estrogen, Sterol Regulatory Element Binding Protein 1, Transcription Factors, Transcriptional Activation
Mol. Endocrinol.
Date: Nov. 01, 2007
PubMed ID: 17636037
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