Regulation of the Liver Fatty Acid-binding Protein Gene by Hepatocyte Nuclear Factor 1α (HNF1α)

Hepatocyte nuclear factor 1α(HNF1α)-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 β-oxidation enzymes (CYP4A3, bifunctional enzyme, and thiolase) were observed in the livers of HNF1α-null mice, whereas hepatic mitochondrial β-oxidation gene (medium and short chain acyl-CoA dehydrogenase) expression levels remain unchanged relative to HNF1α-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 HNF1α-null mice. Isolation and sequence analysis of the 5′-flanking region of the mouse l-FABP gene revealed the presence of two HNF1α regulatory elements. The results of transient transfection studies indicate that HNF1α is required to trans-activate the expression of the l-FABP promoter. Taken together, these data define a critical role for HNF1α 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.