Hepatic functional reserve is an important determining factor for survival in cirrhosis. Since the liver can regenerate during the liver repair response to injury, enhancing residual functional liver mass in diseased liver by stimulating hepatocyte proliferation can accelerate repair and delay liver failure. In Foxm1b transgenic mice or GH-treated mice where premature induction of proliferation-specific Foxm1b transcription factor mediates the expression of S-and M-phase cell cycle genes, hepatocyte proliferation is accelerated during partial hepatectomy. Following bile duct ligation (BDL), bile duct cell proliferation is associated with reduced expression of hepatocyte transcription factor HNF-6. Inducing the expression of liver enriched transcription factor HNF-6 by GH or by recombinant adenovirus expressing HNF-6 cDNA also inhibits the bile duct cell proliferative response to BDL. Activated bile duct cells in turn can directly or indirectly mediate the fibrosis response to biliary obstruction. Using an animal model of biliary obstruction and fibrosis by BDL to reproduce human biliary diseases, we will test the HYPOTHESIS that increasing functional liver mass in biliary-type fibrosis in mice by 1) increasing Foxm1b-mediated hepatocyte regeneration and 2) attenuating liver fibrosis by maintaining hepatic HNF-6 expression to diminish bile duct cell activation of the profibrotic reaction enhances the liver repair response to injury. We will compare hepatocyte and biliary cell proliferation, liver function, liver fibrosis, expression of Foxm1b, HNF-6, cell cycle and profibrosis genes, and survival between Foxm1b transgenic mice with overexpressed Foxm1b in hepatocytes or the Alb-Cre Foxm1b Knock out mice with hepatocyte-specific deletion of Foxm1b Floxed allele with their littermate controls. We will also test the effect of GH-mediated induction of Foxm1b and HNF-6 on the course of biliary obstruction by evaluating similar endpoints. The potential of salvaging failed liver, improving the quality of life or extending survival of patients with liver insufficiency using these therapeutic strategies is far reaching.
