Hepatic expression of cytochrome P450s in hepatocyte nuclear factor 1-alpha (HNF1alpha)-deficient mice

Abstract

Hepatocyte nuclear factor 1 alpha (HNF1alpha) is a liver enriched homeodomain-containing transcription factor that has been shown to transactivate the promoters of several cytochrome P450 (CYP) genes, including CYP2E1, CYP1A2, CYP7A1, and CYP27, in vitro. In humans, mutations in HNF1alpha are linked to the occurrence of maturity onset diabetes of the young type 3, an autosomal dominant form of non-insulin-dependent diabetes mellitus in which afflicted subjects generally develop hyperglycemia before 25 years of age. Mice lacking HNF1alpha also develop similar phenotypes reminiscent of non-insulin-dependent diabetes mellitus. To investigate a potential role for HNF1alpha in the regulation of CYPs in vivo, the expression of major CYP genes from each family was examined in the livers of mice lacking HNF1alpha. Analysis of CYP gene expression revealed marked reductions in expression of Cyp1a2, Cyp2c29 and Cyp2e1, and a moderate reduction of Cyp3a11. In contrast Cyp2a5, Cyp2b10 and Cyp2d9 expression were elevated. There are also significant changes in the expression of genes encoding CYPs involved in fatty acid and bile acid metabolism characterized by a reduction in the expression of Cyp7b1, and Cyp27 as well as elevations in Cyp4a1/3, Cyp7a1, Cyp8b1, and Cyp39a1 expression. These results point to a critical role for HNF1alpha in the regulation of CYPs in vivo and suggest that this transcription factor may have an important influence on drug metabolism as well as lipid and bile acid homeostasis in maturity onset diabetes of the young type 3 diabetics.