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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK070784-01
Application #
6904322
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2005-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$155,000
Indirect Cost
Name
University of Illinois at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Wang, Kewei; Holterman, Ai-Xuan (2012) Pathophysiologic role of hepatocyte nuclear factor 6. Cell Signal 24:9-16
Wang, Kewei; Brems, John J; Gamelli, Richard L et al. (2011) C/EBP? and C/EBP? binding proteins modulate hepatocyte apoptosis through iNOS signaling pathway. Biochim Biophys Acta 1813:1395-403
Wang, Kewei; Brems, John J; Gamelli, Richard L et al. (2011) iNOS/NO signaling regulates apoptosis induced by glycochenodeoxycholate in hepatocytes. Cell Signal 23:1677-85
Glaser, S; Wang, M; Ueno, Y et al. (2010) Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts. Am J Physiol Gastrointest Liver Physiol 299:G769-77
Wang, Kewei; Brems, John J; Gamelli, Richard L et al. (2010) Survivin signaling is regulated through nuclear factor-kappa B pathway during glycochenodeoxycholate-induced hepatocyte apoptosis. Biochim Biophys Acta 1803:1368-75
Wang, Minhua; Chen, Michael; Zheng, Guoqiang et al. (2008) Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice. Am J Physiol Gastrointest Liver Physiol 295:G357-66