TY - JOUR
T1 - Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis
AU - Sanyal, Sabyasachi
AU - Båvner, Ann
AU - Haroniti, Anna
AU - Nilsson, Lisa Mari
AU - Lundåsen, Thomas
AU - Rehnmark, Stefan
AU - Witt, Michael Robin
AU - Einarsson, Curt
AU - Talianidis, Iannis
AU - Gustafsson, Jan Åke
AU - Treuter, Eckardt
PY - 2007/10/2
Y1 - 2007/10/2
N2 - 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 4α (HNF4α), 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 HNF4α-dependent expression of cholesterol 7α hydroxylase (CYP7A1) and sterol 12α 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, HNF4α, 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.
AB - 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 4α (HNF4α), 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 HNF4α-dependent expression of cholesterol 7α hydroxylase (CYP7A1) and sterol 12α 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, HNF4α, 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.
KW - Cholesterol 7α hydroxylase
KW - Farnesoid X receptor
KW - Small heterodimer partner
KW - Sterol 12α hydroxylase
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U2 - 10.1073/pnas.0706736104
DO - 10.1073/pnas.0706736104
M3 - Article
C2 - 17895379
AN - SCOPUS:35648935499
SN - 0027-8424
VL - 104
SP - 15665
EP - 15670
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
ER -