Hepatic nuclear factor

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Ishii, Y., Hansen, A. J., and Mackenzie, P. I. (2000) Octamer transcription factor-1 enhances hepatic nuclear factor-1 alpha-mediated activation of the human UDP glucuronosyltransferase 2B7 promoter. Mol. Pharmacol. 57, 940-947. 

Miao, J., Fang, S., Bae, Y., and Kemper, J. K. (2006) Functional inhibitory crosstalk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-lalpha. J. Biol. Chem. 281, 14537-14546. 

Wortham, M., Czerwinski, M., He, L., Parkinson, A., and Wan, Y. J. (2007) Expression of constitutive androstane receptor, hepatic nuclear factor 4 alpha, and P450 oxidore-ductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver. Drug Metab. Dispos. 35, 1700-1710. 

Hertz, R., Magenheim, J., Berman, I., and Bar-Tana, J. (1998) Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature 392, 512-516. 

A. Pinelli, G. Galli, and M. Crestani (2001). The negative effects of bile acids and tumor necrosis factor-a on the transcription of cholesterol 7a-hydroxylase gene (CYP7AI) converge to hepatic nuclear factor-4 A novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. J. Biol. Chem. 276, 30708-30716. 

Tsai, Tsai O Malley, 1991). These elements have a core sequence of an imperfect repeat A/GGGTCA, separated by a single nucleotide (GTGTCAAAG-GTCAAA). COUP-TF is a 45 kDa protein able to bind to many different A/GGGTCA repeats, which are also bound by dihydroxycalciferol, thyroid and retinoic acid receptors (Cooney et al, 1993) and can activate or repress transcription depending on the promoter context. It has been found in a number of different tissues in different species. Hepatic nuclear factor (HNF-4) is another orphan member of this superfamily. 

Grajer, K.-H., Horlein, A. Igo-Kemenes, T. (1993). Hepatic nuclear factor lot (HNF-lot) is expressed in the oviduct of hens and interacts with regulatory elements of the lysozyme gene. Biol. Chem. Hoppe-Seyler, 374, 319-26. 

Holloway MG, Laz EV, Waxman DJ (2006) Codependence of growth hormone-responsive, sexually dimorphic hepatic gene expression on signal transducer and activator of transcription 5b and hepatic nuclear factor 4a. Mol Endocrinol 20 647-660... 

Liver Trovafloxacin was withdrawn from the European market because of Uver toxicity and acute liver failure in 1999, but it is still available under very strong restrictions in the USA. In experiments in isolated human hepatocytes trovafloxacin inhibited expression of hepatic nuclear factor-4a (HNF-4ot), which in turn suppressed the function of a network of genes that govern major metabolic processes, lipid and carbohydrate metabolism, and mitochondrial biol-ogy [78 ]. The author concluded that this is the probable underlying mechanism of trovafloxacin-induced hepatotoxicity. 

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