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Hepatocyte Nuclear Factor (HNF) 1 and HNF4 Mediate Hepatic Multidrug Resistance Protein 2 Up-Regulation during Hepatitis C Virus Gene Expression

Department of Pediatrics and Graduate Program in Toxicology (I.Q.) and Division of Gastroenterology/Hepatology (M.I., F.R.S.), University of Colorado Health Sciences Center, Aurora, Colorado; and Laboratory of Molecular Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland (G.A.K.-U.)

Hepatitis C virus (HCV) is known to induce hepatic oxidative stress that is implicated in the up-regulation of multidrug resistance proteins (MRPs). The relationship between increased prooxidant production, MRPs, and HCV has not been investigated. Here, we report that a homeodomain-containing transcription factor, hepatocyte nuclear factor (HNF) 1, plays a central role in liver gene regulation during HCV gene expression and/or subgenome replication. MRP2 protein and mRNA expression were increased and MRP2 promoter activity was increased 7-fold. Mutations within the putative HNF1 binding site of the human MRP2 promoter abrogated HCV-induced activation, implicating HNF1 in the induction of MRP2 by HCV. The mechanism by which HNF1-mediated activation occurs seems to be transcriptional, because the regulated expression of HNF4, which is known to control HNF1 expression, was also increased. Consistent with this finding, HNF1 mRNA was increased 10-fold. A promoter-luciferase construct of the human HNF1 gene was activated in an HNF4-dependent manner, and a mutant construct lacking the HNF4 binding site was not activated in HCV-positive cells. Consistent with this hypothesis, HNF4 protein and mRNA levels as well as HNF4 promoter activity and DNA binding activity were increased. The expression of HNF1 seems to play a critical role in the induction of hepatic MRP2 secondary to HCV subgenomic replication. The ability of HCV to induce HNF1 and HNF4 is attributed to 1) increased oxidative stress and 2) direct protein-protein interactions between HCV nonstructural component (NS) 5A and HNF1, leading to enhanced HNF1 DNA binding. In conclusion, we describe a novel mechanism by which HCV gene expression may induce adaptive responses involving MRP2 via HNF1 activation. This may constitute, in part, the cellular detoxification task force during HCV infection.

Address correspondence to: Dr. Ishtiaq Qadri, Department of Pediatrics, University of Colorado Health Sciences Center, Mail Stop 8106, 12801 East 17th Ave., L-18-7403, RC-1 South, P.O. Box 6511, Aurora, CO 80045. E-mail: ishtiaq.qadri{at}uchsc.edu