Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis.
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 4alpha (HNF4alpha), 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 HNF4alpha-dependent expression of cholesterol 7alpha hydroxylase (CYP7A1) and sterol 12alpha 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, HNF4alpha, 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.
Sanyal
Sabyasachi
S
Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital, S-14157 Huddinge, Sweden. sabyasachi.sanyal@biosci.ki.se
Båvner
Ann
A
Haroniti
Anna
A
Nilsson
Lisa-Mari
LM
Lundåsen
Thomas
T
Rehnmark
Stefan
S
Witt
Michael Robin
MR
Einarsson
Curt
C
Talianidis
Iannis
I
Gustafsson
Jan-Ake
JA
Treuter
Eckardt
E
D001647:Bile Acids and Salts / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C103316:GPS2 protein, human