In vivo regulation of murine CYP7A1 by HNF-6: a novel mechanism for diminished CYP7A1 expression in biliary obstruction.
Disruption of the enterohepatic bile acid circulation during biliary tract obstruction leads to profound perturbation of the cholesterol and bile acid metabolic pathways. Several families of nuclear receptor proteins have been shown to modulate this critical process by regulating hepatic cholesterol catabolism and bile acid synthesis through the transcriptional control of cholesterol 7-alpha hydroxylase (CYP7A1). Hepatocyte nuclear factor (HNF) 6 (also known as OC-1) is a member of the ONECUT family of transcription factors that activate numerous hepatic target genes essential to liver function. We have previously shown that hepatic expression of mouse HNF-6 messenger RNA (mRNA) and protein significantly decrease following bile duct ligation. Because CYP7A1 contains potential HNF-6 binding sites in its promoter region, we tested the hypothesis that HNF-6 transcriptionally regulates CYP7A1. Following bile duct ligation, we demonstrated that diminished HNF-6 mRNA levels correlate with a reduction in CYP7A1 mRNA expression. Increasing hepatic levels of HNF-6 either by infection with recombinant adenovirus vector expressing HNF-6 cDNA by growth hormone treatment leads to an induction of CYP7A1 mRNA. To directly evaluate if HNF-6 is a transcriptional activator for CYP7A1, we used deletional and mutational analyses of CYP7A1 promoter sequences and defined sequences -206/-194 to be critical for CYP7A1 transcriptional stimulation by HNF-6 in cotransfection assays. In conclusion, the HNF-6 protein is a component of the complex network of hepatic transcription factors that regulates the expression of hepatic genes essential for bile acid homeostasis and cholesterol/lipid metabolism in normal and pathological conditions.
Wang
Minhua
M
Department of Surgery, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA.
Tan
Yongjun
Y
Costa
Robert H
RH
Holterman
Ai-Xuan L
AX
D000818:Animals; D001483:Base Sequence; D002779:Cholestasis / Q000201:enzymology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000494:pharmacology; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; C496606:Onecut1 protein, mouse; D015534:Trans-Activators; D013006:Growth Hormone; D002790:Cholesterol 7-alpha-Hydroxylase