Pathophysiological role of hepatocyte nuclear factor 6 (HNF6) during cholestatic liver injury

Animal models of parenchymal liver injury by bile duct ligation (BDL) and all forms of liver diseases including neonatal hepatitis and clinical obstructive cholangiopathies such as biliary atresia have the pathological features of cholestasis and liver dysfunction. Hepatocyte nuclear factors 6 (HNF6) is important to the transcriptional regulation, expression and function of essential hepatic genes involved in the differentiated as well as the adaptive response to liver injury. Using HNF6 conditional knock out mice where HNF6 is functionally deleted in the liver, we established that HNF6 is required for proper liver function of cholesterol clearance, improvement of cholestasis and hepatocyte regeneration. Enhancing HNF6 expression in wild type mice also diminished hepatic apoptosis and fibrosis. In this proposal, we propose to further characterize the biological function of HNF6 by testing the HYPOTHESIS that HNF6 direct transcriptional regulation of antiapoptotic and antifibrotic pathways contributes to hepatoprotection during bile duct injury. This hypothesis will be tested in two specific aims. Livers were isolated from wild-type (WT) and HNF6 knockout (KO) mice respectively. Liver samples were processed via ChIP protocol using monoclonal HNF6 or IgG antibodies (control). ChIP-DNA was further processed by Affymetrix Procedure H. The following samples are PCR products: (1) wild-type liver 1 & HNF6 antibody; (2) wild-type liver 2 & HNF6 antibody; (3) wild-type liver 1 & IgG antibody; (4) wild-type liver 2 & IgG antibody; (5) HNF6-knockout liver 1 & HNF6 antibody; (6) HNF6-knockout liver 1 & HNF6 antibody.