Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP
| Autor: | Krister Bamberg, Andy Greenfield, Konstantinos Boulias, Iannis Talianidis, Nitsa Katrakili, Peter Underhill |
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| Rok vydání: | 2005 |
| Předmět: |
animal structures
Receptors Cytoplasmic and Nuclear Repressor Mice Transgenic chemical and pharmacologic phenomena Biology Article General Biochemistry Genetics and Molecular Biology Biological pathway Mice Bile acid conjugation Animals RNA Messenger Molecular Biology Psychological repression Regulation of gene expression General Immunology and Microbiology General Neuroscience hemic and immune systems Chromatin Repressor Proteins Gene Expression Regulation Liver Biochemistry embryonic structures Small heterodimer partner biological phenomena cell phenomena and immunity Chromatin immunoprecipitation |
| Zdroj: | The EMBO Journal. 24:2624-2633 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.1038/sj.emboj.7600728 |
| Popis: | SHP (small heterodimer partner) is an important component of the feedback regulatory cascade, which controls the conversion of cholesterol to bile acids. In order to identify the bona fide molecular targets of SHP, we performed global gene expression profiling combined with chromatin immunoprecipitation assays in transgenic mice constitutively expressing SHP in the liver. We demonstrate that SHP affects genes involved in diverse biological pathways, and in particular, several key genes involved in consecutive steps of cholesterol degradation, bile acid conjugation, transport and lipogenic pathways. Sustained expression of SHP leads to the depletion of hepatic bile acid pool and a concomitant accumulation of triglycerides in the liver. The mechanism responsible for this phenotype includes SHP-mediated direct repression of downstream target genes and the bile acid sensor FXRalpha, and an indirect activation of PPARgamma and SREBP-1c genes. We present evidence for the role of altered chromatin configurations in defining distinct gene-specific mechanisms by which SHP mediates differential transcriptional repression. The multiplicity of genes under its control suggests that SHP is a pleiotropic regulator of diverse metabolic pathways. |
| Databáze: | OpenAIRE |
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