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The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants. 2.7 A X-ray crystalography results suggest that the HNF4s may be transcription factors that are constitutively bound to fatty acids. A comparision of gene expression patterns induced by hepatic nuclear factors, HNF6, HNF4alpha and HNF1beta, in a pancreatic beta- cell line. A study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. Association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q. Control transcription of aldehyde dehydrogenase 2. Cotransfection with an HNF-4alpha expression vector demonstrated a direct activation of the ALPI promoter through -94 to -82 element. Data show that nitric oxide and transforming growth factor-beta1 inhibit hepatocyte nuclear factor-4alpha function in HEPG2 cells. HNF-4 and FXR, are closely involved in MTP gene expression, and the results provide evidence for a novel interaction between bile acids and lipoprotein metabolism. HNF-4alpha has a role in regulating gluconeogenic genes along with PGC-1 and SREBP-1. HNF-4alpha is involved in regulating cancer cell transmigration by modulating the Fas-FasL system. HNF-4alpha is linked to late-onset type 2 diabetes. HNF-4alpha plays an important role in the differentiation and maintenance of the matured human hepatocyte phenotype. HNF-4alpha represents a potential modifier of the glycerol kinase deficiency phenotype. HNF4 alpha activates the insulin gene directly, through a previously unrecognized cis element. HNF4 alpha isoforms originating from the P1 promoter exhibit stronger transcriptional activities and recruit coactivators more efficiently than isoforms driven by the P2 promoter. HNF4-alpha, HNF3-beta and Sp1/Sp3 are important in regulation of prothrombin expression. HNF4alpha as a major factor for the control of UGT1A9 hepatic expression. Hepatic expression of HNF-4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels. Human SNPs were identified across a 78-kb region around HNF4 alpha and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetics and controls. In the present study, we investigated the expression of HNF4alpha in beta-cells and examined its functional properties. In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes. MODY is caused by a translocation at chromosome 20, resulting in an upstream disruption of the gene. Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene. Results suggest that the transcriptional cross talk between the TGFbeta-regulated Smads 3 and 4 and hepatocyte nuclear factor-4 is mediated by specific functional domains in the two types of transcription factors. Single nucleotide polymorphisms of HNF4-alpha associated with the risk of type 2 diabetes are evaluated. The HNF-4alpha clinical phenotype and beta cell dysfunction are similar to HNF-1alpha in maturity onset diabetes in the young. The missense mutation was located in the DNA binding domain of HNF4A, and identification of this mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. These results support clinical findings that liver function can also be impaired in diabetic patients having hepatocyte nuclear factor 4alpha (HNF4alpha) mutations. Transdifferentiation to the hepatocytic phenotype in hepatoid adenocarcinoma tissue of the stomach was not directly associated with HNF-4alpha expression, thus suggesting that transdifferentiation proceeds by a complicated mechanism. Twenty different mutations in the HNF-4alpha, GCK and HNF-1alpha in 29 families. Three of 3, 10 of 11 and 1 of 6 of the mutations identified in HNF-4alpha, GCK and HNF-1alpha respectively, were new. Variants in both the P1 and P2 promoters of HNF4A increase risk for typical type 2 diabetes. Analysis of amino acids involved in coactivator and ligand interactions in hepatocyte nuclear factor-4alpha. Cooperative role with Sp1 or Sp3 leads to transcriptional activation of the human haem oxygenase-1 gene promoter in a hepatoma cell line. Hepatocyte nuclear factor-4 binds to SREBP2 to enhance sterol isomerase gene expression in hepatocytes. Human microsomal triglyceride transfer protein is transcriptionally regulated by hepatocyte nuclear factor-4alpha. Identifed systematically the genes occupied by the transcriptional regulators HNF1alpha, HNF4alpha, and HNF6, together with RNA polymerase II in liver and pancreatic islets; results suggest how misregulation of HNF4alpha can contribute to type 2 diabetes. Ligand-activated PXR interferes with HNF-4 signaling by targeting the common coactivator PGC-1, which underlies physiologically relevant inhibitory cross-talk between drug metabolism and cholesterol/glucose metabolism. Mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. Regulates transcription of hepatitis B virus. Relative prevalence of 3% of MODY1 (two different mutations in two families), 10% of MODY2 (seven in eight), and 36% of MODY3 (21 in 28) among Danish kindred clinically diagnosed as MODY. Residues of the ligand binding pocket are critical in hepatocyte nuclear factor-4alpha. Role in regulating CYP7A1. Spermine significantly enhanced the interaction between HNF4alpha and full-length DRIP205 in an AF-2, NR-box-dependent manner. Spermine enhanced the interaction of DRIP205 with the VDR , but decreased the interaction of both HNF4alpha and VDR with GRIP1. Stimulated expression of the precore RNA and the core RNA from the core promoter of both the wild-type (WT) Hepatitis B virus and the double mutant, although its effect on the former was more prominent. The V199I missense mutation located in the ligand binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in a Philippine-1 family. The order of recruitment of factors to the HNF-4alpha regulatory regions upon the initial activation of the gene during enterocyte differentiation. Variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes.
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