Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Abstract

Coordinated regulation of bile acid biosynthesis, the predominant pathway for hepatic cholesterol catabolism, is mediated by few key nuclear receptors including the orphan receptors liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), small heterodimer partner (SHP), and the bile acid receptor FXR (farnesoid X receptor). Activation of FXR initiates a feedback regulatory loop via induction of SHP, which suppresses LRH-1-and HNF4␣-dependent expression of cholesterol 7␣ hydroxylase (CYP7A1) and sterol 12␣ hydroxylase (CYP8B1), the two major pathway enzymes. Here we dissect the transcriptional network governing bile acid biosynthesis in human liver by identifying GPS2, a stoichiometric subunit of a conserved corepressor complex, as a differential coregulator of CYP7A1 and CYP8B1 expression. Direct interactions of GPS2 with SHP, LRH-1, HNF4␣, and FXR indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes. In addition, species-specific differences in the regulation of bile acid biosynthesis were uncovered by identifying human CYP8B1 as a direct FXR target gene, which has implications for therapeutic approaches in bile acid-related human disorders.cholesterol 7␣ hydroxylase ͉ sterol 12␣ hydroxylase ͉ farnesoid X receptor ͉ small heterodimer partner B ile acids (BAs) are cholesterol derivatives essential for absorption of dietary lipids and fat-soluble vitamins and maintenance of cholesterol BA homeostasis (1, 2). In humans the major BA biosynthetic pathway is initiated by cholesterol 7␣ hydroxylase (CYP7A1) to produce two primary BAs, cholic acid and chenodeoxycholic acid (CDCA). Sterol 12␣ hydroxylase (CYP8B1) catalyzes the synthesis of cholic acid and determines the ratio of cholic acid to CDCA in the bile (1). In addition to emulsification of dietary lipids, cholic acid and CDCA are ligands for farnesoid X receptor (FXR/NR1H4) (3-5). Ligandbound FXR regulates a number of target genes involving BA transport and metabolism (6). BAs also feedback-regulate BA biosynthesis, where activated FXR induces small heterodimer partner (SHP/NR0B2) gene expression, and SHP in turn inhibits liver receptor homolog 1 (LRH-1/NR5A2) or hepatocyte nuclear factor 4␣ (HNF4␣/NR2A1) activities on the BA response elements (BAREs) of CYP7A1 and CYP8B1 promoters (7-10). BAs can also act via FXR-independent pathways that use PKC (11) and JNK signaling (12, 13) to suppress HNF4␣-mediated expression of human CYP8B1 (hCYP8B1) (10,11,14). Although the physiological role of SHP in BA biosynthesis is well documented, mechanistic details of repression by SHP remain unclear. Recent studies indicate that SHP may repress its targets (i) via direct binding and blocking the coactivator interaction interface of its target nuclear receptors (NRs), (ii) by antagonizing CREB binding protein (CBP)/p300-dependent coactivator functions on NRs via recruitment of a coinhibitor protein like EID1, and (iii) by recruiting corepressor complexes that include histone deacetylases (HDAC) 1, 3, and 6, Sin3A...

Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr −/− mice versus hamsters

“…In agreement with previous in vivo and in vitro studies in humans, the present work suggests that the SHP-dependent mechanism for regulating CYP8B1 by FXR agonists in hamsters is considerably less effective than the regulation of the same gene in mice and rats ( 67 ). Various mechanisms have been proposed for the reduced effect of BA on the expression CYP8B1 in humans compared with rats ( 22,67,68 ). If these are also proven to apply in hamsters, then the hamster may be an even better model for human BA metabolism than it was previously considered.…”

Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR−/− and apoE−/− mice

“…Human bile acid physiology and regulation have notable differences from mouse. Of particular relevance here, FXR represses CYP8B1 expression via induction of SHP in mouse, whereas FXR directly stimulates CYP8B1 expression through an FXR response element in humans (50). Whether these species differences will attenuate the protective effect of FXR agonists against dyslipidemia or atherosclerosis in humans will require further study.…”

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

“…basis for ligand-independent repression by the repressor class of orphan nuclear receptors because they do not rely on the traditional nuclear receptor corepressors NCoR and SMRT to drive gene inhibition. Rather, they recruit other types of corepressors to execute their repressive activity (Bavner et al 2002;Boulias and Talianidis 2004;Wang et al 2006;Zhang et al 2006;Sanyal et al 2007;Takezawa et al 2007;Yokoyama et al 2008). Crystal structures of several repressive orphan nuclear receptors determined to date reveal a common structural feature, termed the autorepressed conformation (Wang et al 2003;Flaig et al 2005;Kruse et al 2008;Sablin et al 2008;Zhou et al 2011;Tan et al 2013;Zhi et al 2014), in which helix H12 is packed into the canonical coactivatorbinding groove, thus preventing both coactivators and corepressors from binding to this site.…”