Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP

K Boulias, N Katrakili, K Bamberg, P Underhill… - The EMBO …, 2005 - embopress.org
K Boulias, N Katrakili, K Bamberg, P Underhill, A Greenfield, I Talianidis
The EMBO journal, 2005embopress.org
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 …
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 FXRα, and an indirect activation of PPARγ 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.
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