Regulation of the liver fatty acid-binding protein gene by hepatocyte nuclear factor 1alpha (HNF1alpha). Alterations in fatty acid homeostasis in HNF1alpha-deficient mice

Abstract

Hepatocyte nuclear factor 1alpha (HNF1alpha)-null mice have enlarged fatty livers and alterations in the expression of genes encoding enzymes involved in the synthesis, catabolism, and transport of fatty acids. Elevations in the expression of genes encoding fatty acid synthetic enzymes (fatty acid synthase and acyl-CoA carboxylase) and peroxisomal beta-oxidation enzymes (CYP4A3, bifunctional enzyme, and thiolase) were observed in the livers of HNF1alpha-null mice, whereas hepatic mitochondrial beta-oxidation gene (medium and short chain acyl-CoA dehydrogenase) expression levels remain unchanged relative to HNF1alpha-heterozygous controls. An elevation in the levels of fatty acid transporter gene expression was also observed. In contrast, there was a marked reduction of liver fatty acid-binding protein (l-FABP) gene expression in the livers of HNF1alpha-null mice. Isolation and sequence analysis of the 5'-flanking region of the mouse l-FABP gene revealed the presence of two HNF1alpha regulatory elements. The results of transient transfection studies indicate that HNF1alpha is required to trans-activate the expression of the l-FABP promoter. Taken together, these data define a critical role for HNF1alpha in the pathogenesis of a phenotype marked by fatty infiltration of the liver and in the regulation of the l-FABP gene, the expression of which may have a direct impact on the maintenance of fatty acid homeostasis.