Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice.
Growth hormone (GH) function is mediated through multiple endocrine pathways. In the liver, GH also transcriptionally activates hepatocyte nuclear factor-6 (HNF-6; OC-1), a liver-enriched transcription factor that regulates the expression of genes essential to hepatic function. We hypothesize that GH modulates hepatic function in the normal and injured liver through HNF-6 and HNF-6 target genes. CD1 mice received PBS or GH for the 1-, 7-, and 28-day course of Sham operation or bile duct ligation (BDL). Proliferation-, metabolic-, and profibrotic-specific hepatic functions were assessed with a focus on candidate HNF-6 transcriptional target genes. Confirmation of HNF-6 regulation was done by analysis of target gene expression in liver infected with recombinant adenovirus AdHNF-6 expression vectors. GH administration upregulated HNF-6 expression throughout the course of liver injury. This was associated with increased expression of HNF-6 proliferative target genes cyclin D1 and metabolic gene Cyp7A1 and downregulation of profibrogenic TGFb2R. Hepatic function improved such as enhanced hepatocyte proliferation, higher cholesterol clearance throughout the course of injury, and attenuated fibrogenic response at day 28 of BDL. GH treatment also transcriptionally increased albumin expression in an HNF-6-independent manner. This was associated with enhanced serum albumin levels. In conclusion, the GH/HNF-6 axis is a potential in vivo mechanism underlying GH diverse function in the liver to modulate the liver repair response to BDL.
RUSH Univ. Medical Center, Depts. of Pediatrics and Surgery, 1725 W. Harrison St., Suite 718, Chicago, IL, USA.
Minhua
M
Wang
Michael
M
Chen
Guoqiang
G
Zheng
Barney
B
Dillard
Mike
M
Tallarico
Zorayda
Z
Ortiz
Ai-Xuan
AX
Holterman
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D001651:Cholestasis, Extrahepatic / Q000503:physiopathology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis; D051559:Hepatocyte Nuclear Factor 6 / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D008026:Ligation; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D027981:Symporters / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D056741:Cyclin D; D016213:Cyclins; D051559:Hepatocyte Nuclear Factor 6; C496606:Onecut1 protein, mouse; D029363:Organic Anion Transporters, Sodium-Dependent; D011994:Recombinant Proteins; D027981:Symporters; D019382:Human Growth Hormone; C071908:sodium-bile acid cotransporter; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse