Regulation of the liver fatty acid-binding protein gene by hepatocyte nuclear factor 1 alpha (HNF1 alpha) - Alterations in fatty acid homeostasis in HNF1 alpha-deficient mice

Hepatocyte nuclear factor 1 alpha (HNF1 alpha)-null mice have enlarged fatt y livers and alterations in the expression of genes encoding enzymes involv ed in the synthesis, catabolism, and transport of fatty acids. Elevations i n the expression of genes encoding fatty acid synthetic enzymes (fatty acid synthase and acyl-CoA carboxylase) and peroxisomal B-oxidation enzymes (CY P4A3, bifunctional enzyme, and thiolase) were observed in the livers of HNF 1 alpha-null mice, whereas hepatic mitochondrial p-oxidation gene (medium a nd short chain acyl-CoA dehydrogenase) expression levels remain unchanged r elative to HNF1 alpha-heterozygous controls. An elevation in the levels of fatty acid transporter gene expression was also observed. In contrast, ther e was a marked reduction of liver fatty acid-binding protein (L-FABP) gene expression in the livers of HNF1 alpha-null mice. Isolation and sequence an alysis of the 5'-flanking region of the mouse L-FABP gene revealed the pres ence of two HNF1 alpha regulatory elements. The results of transient transf ection studies indicate that HNF1 alpha is required to transactivate the ex pression of the L-FABP promoter. Taken together, these data define a critic al role for HNF1 alpha in the pathogenesis of a phenotype marked by fatty i nfiltration of the liver and in the regulation of the L-FABP gene, the expr ession of which may have a direct impact on the maintenance of fatty acid h omeostasis.