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Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP
Author(s) -
Boulias Konstantinos,
Katrakili Nitsa,
Bamberg Krister,
Underhill Peter,
Greenfield Andy,
Talianidis Iannis
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600728
Subject(s) - biology , foundation (evidence) , library science , history , archaeology , computer science
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 FXR α, and an indirect activation of PPAR γ 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.