SREBP-1 Interacts with Hepatocyte Nuclear Factor-4α and Interferes with PGC-1 Recruitment to Suppress Hepatic Gluconeogenic Genes
Copyright policy )SREBP-1 Interacts with Hepatocyte Nuclear Factor-4α and Interferes with PGC-1 Recruitment to Suppress Hepatic Gluconeogenic Genes
The hepatocyte nuclear factor-4alpha (HNF-4alpha)/PGC-1 pathway plays a crucial role in the transcriptional regulation of hepatic gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and Glc-6-Pase, genes that are activated at fasting and suppressed in a fed state. SREBP-1c dominates the nutritional regulation of lipogenic genes inverse to gluconeogenesis. Here we show the mechanism by which SREBP-1 suppresses expression of gluconeogenic genes. A series of luciferase reporter assays demonstrated that SREBP-1a and -1c effectively inhibited the PEPCK promoter activity that was induced by HNF-4alpha. The HNF-4alpha-binding site in the glucocorticoid-response unit was responsible for the SREBP-1 inhibition, although SREBP-1 did not bind to the PEPCK promoter as demonstrated by electrophoretic mobility shift assays. The inhibitory effect was more potent in the isoform of SREBP-1a than SREBP-1c and was eliminated by deletion of the amino-terminal transactivation domain of SREBP-1. Coimmunoprecipitation experiments demonstrated that these two transcription factors directly interact through the transactivation domain of SREBP-1 and the ligand binding/AF2 domains of HNF-4alpha. Estimation of coactivator recruitment using HNF-4alpha-Gal4DBD fusion assay showed that SREBP-1 competitively inhibited PGC-1 recruitment, a requirement for HNF-4alpha activation. Consistent with these results, hepatic PEPCK and Glc-6-Pase mRNA levels are suppressed by overexpression of SREBP-1a and -1c in the transgenic mice. Our data indicate that SREBP-1 has a novel role as negative regulator of gluconeogenic genes through a cross-talk with HNF-4alpha interference with PGC-1 recruitment.
- University of Tokyo Japan
- University of Tsukuba Japan
Binding Sites, Dose-Response Relationship, Drug, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Colforsin, Mice, Transgenic, Blotting, Northern, Ligands, Binding, Competitive, Cell Line, DNA-Binding Proteins, Lipoproteins, LDL, Mice, Gene Expression Regulation, Hepatocyte Nuclear Factor 4, Liver, CCAAT-Enhancer-Binding Proteins, Animals, Humans, Luciferases, Glutathione Transferase
Binding Sites, Dose-Response Relationship, Drug, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Colforsin, Mice, Transgenic, Blotting, Northern, Ligands, Binding, Competitive, Cell Line, DNA-Binding Proteins, Lipoproteins, LDL, Mice, Gene Expression Regulation, Hepatocyte Nuclear Factor 4, Liver, CCAAT-Enhancer-Binding Proteins, Animals, Humans, Luciferases, Glutathione Transferase
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