Genomes and Genes
hepatocyte nuclear factor 4
Summary: A subfamily of nuclear receptors that regulate GENETIC TRANSCRIPTION of a diverse group of GENES involved in the synthesis of BLOOD COAGULATION FACTORS; and in GLUCOSE; CHOLESTEROL; and FATTY ACIDS metabolism.
- Li X, Jiang H, Qu L, Yao W, Cai H, Chen L, et al. Hepatocyte nuclear factor 4? and downstream secreted phospholipase A2 GXIIB regulate production of infectious hepatitis C virus. J Virol. 2014;88:612-27 pubmed publisher..b>Hepatocyte nuclear factor 4? (HNF4?), the most abundant transcription factor in the liver, regulates the VLDL secretory pathway...
- Chandra V, Holla P, Ghosh D, Chakrabarti D, Padigaru M, Jameel S. The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4. PLoS ONE. 2011;6:e22412 pubmed publisher..genes down regulated in pORF3-expressing cells were found to be under regulation of the liver-enriched hepatocyte nuclear factor 4 (HNF4), which regulates hepatocyte-specific gene expression...
- Niehof M, Borlak J. EPS15R, TASP1, and PRPF3 are novel disease candidate genes targeted by HNF4alpha splice variants in hepatocellular carcinomas. Gastroenterology. 2008;134:1191-202 pubmed publisher..We report induction of P2 promoter-driven HNF4alpha splice variants and regulation of disease candidate genes in EGF-induced mouse and human HCC. ..
- Thanabalasingham G, Shah N, Vaxillaire M, Hansen T, Tuomi T, GaÅ¡perÃkovÃ¡ D, et al. A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia. 2011;54:2801-10 pubmed publisher..in individuals with HNF1A-MODY (nâ€‰=â€‰457), glucokinase (GCK)-MODY (nâ€‰=â€‰404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (nâ€‰=â€‰54) and type 2 diabetes (nâ€‰=â€‰582) from seven ..
- Oishi T, Date S, Shimamoto Y, Saito T, Hirota K, Sugaya T, et al. A nuclear receptor, hepatocyte nuclear factor 4, differently contributes to the human and mouse angiotensinogen promoter activities. J Recept Signal Transduct Res. 2010;30:484-92 pubmed publisher..We previously showed, in hepatoma-derived HepG2 cells that a hepatocyte nuclear factor 4 (HNF4) potentiated human AGT (hAGT) promoter activity and identified its binding sites (termed regions ..
- Sugai M, Umezu H, Yamamoto T, Jiang S, Iwanari H, Tanaka T, et al. Expression of hepatocyte nuclear factor 4 alpha in primary ovarian mucinous tumors. Pathol Int. 2008;58:681-6 pubmed publisherb>Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a member of the nuclear receptor superfamily and is expressed in several endodermal tissues...
- Martinez Jimenez C, Kyrmizi I, Cardot P, Gonzalez F, Talianidis I. Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol. 2010;30:565-77 pubmed publisher..These results establish the fundamental role of dynamic regulatory interactions between HNF4alpha, Hes6, PPARalpha, and PPARgamma in the coordinated expression of genes involved in fatty acid transport and metabolism. ..
- Wang H, Ho P, Lan C, Chang M. Transcriptional regulation of human eosinophil RNase2 by the liver-enriched hepatocyte nuclear factor 4. J Cell Biochem. 2009;106:317-26 pubmed publisher..Our results provide novel mechanisms for HNF4 function as an activator to regulate edn promoter activity, which account for differential transcription regulation of human eosinophil RNases. ..
- Grigo K, Wirsing A, Lucas B, Klein Hitpass L, Ryffel G. HNF4 alpha orchestrates a set of 14 genes to down-regulate cell proliferation in kidney cells. Biol Chem. 2008;389:179-87 pubmed publisher..The cell-specific transcription factor hepatocyte nuclear factor 4 alpha (HNF4 alpha) is down-regulated in RCC and we have shown that HNF4 alpha inhibits cell ..
- Sugawara H, Iwata H, Souri M, Ichinose A. Regulation of human protein Z gene expression by liver-enriched transcription factor HNF-4alpha and ubiquitous factor Sp1. J Thromb Haemost. 2007;5:2250-8 pubmed..These findings provide the first step toward understanding the mechanisms of the varying plasma PZ levels in individuals under physiological and pathological conditions. ..
- Ellard S, Bellanne Chantelot C, Hattersley A. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008;51:546-53 pubmed publisher..Best practice guidelines have been established for monogenic forms of diabetes caused by mutations in the GCK, HNF1A and HNF4A genes. The guidelines include both diagnostic and predictive genetic tests and interpretation of the results. ..
- Zhang Y, Bonzo J, Gonzalez F, Wang L. Diurnal regulation of the early growth response 1 (Egr-1) protein expression by hepatocyte nuclear factor 4alpha (HNF4alpha) and small heterodimer partner (SHP) cross-talk in liver fibrosis. J Biol Chem. 2011;286:29635-43 pubmed publisher..Here we show that Egr-1 expression is tightly regulated by nuclear receptor signaling. Hepatocyte nuclear factor 4Î± (HNF4Î±) activated the Egr-1 promoter through three DR1 response elements as identified by trans-..
- Hoffman B, Robertson G, Zavaglia B, Beach M, Cullum R, Lee S, et al. Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver. Genome Res. 2010;20:1037-51 pubmed publisher..Finally, we apply these approaches to generate novel insights into how FOXA2, PDX1, and HNF4A cooperate to drive islet- and liver-specific gene expression. ..
- Schmidt D, Wilson M, Ballester B, Schwalie P, Brown G, Marshall A, et al. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science. 2010;328:1036-40 pubmed publisher..determine experimentally the genome-wide occupancy of two TFs, CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha, in the livers of five vertebrates...
- Lee J, Lees C, Prescott N, Anderson C, Phillips A, Wesley E, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009;41:1330-4 pubmed publisher..The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis. ..
- Wang Z, Bishop E, Burke P. Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4?. BMC Genomics. 2011;12:128 pubmed publisherb>Hepatocyte nuclear factor 4? (HNF4?), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response...
- Ahn S, Shah Y, Inoue J, Morimura K, Kim I, Yim S, et al. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:908-20 pubmed publisher..While HNF4alpha does not have a major role in normal function of the intestine, it protects the gut against DSS-induced colitis. ..
- Palanker L, Tennessen J, Lam G, Thummel C. Drosophila HNF4 regulates lipid mobilization and beta-oxidation. Cell Metab. 2009;9:228-39 pubmed publisher..Taken together, our results support a feed-forward model for dHNF4, in which fatty acids released from triglycerides activate the receptor, inducing enzymes that drive fatty acid oxidation for energy production. ..
- Wang Z, Burke P. Modulation of hepatocyte nuclear factor-4alpha function by the peroxisome-proliferator-activated receptor-gamma co-activator-1alpha in the acute-phase response. Biochem J. 2008;415:289-96 pubmed publisher..These results establish the importance of PGC-1alpha for HNF-4alpha function and describe a new HNF-4alpha-dependent regulatory mechanism that is involved in the response to injury. ..
- Chen E, Gong D, Leng X, Bai L, Liu C, Wang L, et al. Inhibiting the expression of hepatocyte nuclear factor 4 alpha attenuates lipopolysaccharide/D-galactosamine-induced fulminant hepatic failure in mice. Hepatobiliary Pancreat Dis Int. 2012;11:624-9 pubmedb>Hepatocyte nuclear factor 4 alpha (HNF4alpha) plays an important role in regulating cytokine-induced inflammatory responses...
- Iwazaki N, Kobayashi K, Morimoto K, Hirano M, Kawashima S, Furihata T, et al. Involvement of hepatocyte nuclear factor 4 alpha in transcriptional regulation of the human pregnane X receptor gene in the human liver. Drug Metab Pharmacokinet. 2008;23:59-66 pubmed..These results suggested that HNF4alpha transactivated the human PXR gene by binding to the DR1 element located at -88/-76 of the promoter and was involved in the expression of PXR in the human liver. ..
- Xie X, Liao H, Dang H, Pang W, Guan Y, Wang X, et al. Down-regulation of hepatic HNF4alpha gene expression during hyperinsulinemia via SREBPs. Mol Endocrinol. 2009;23:434-43 pubmed publisher..These findings also provide new insights into diabetes-associated complications such as fatty liver disease. ..
- Qadri I, Hu L, Iwahashi M, Al Zuabi S, Quattrochi L, Simon F. Interaction of hepatocyte nuclear factors in transcriptional regulation of tissue specific hormonal expression of human multidrug resistance-associated protein 2 (abcc2). Toxicol Appl Pharmacol. 2009;234:281-92 pubmed publisher..The coordinated regulation of xenobiotic transporters and oxidative conjugation may determine the adaptive responses to cellular detoxification processes...
- Chen M, Lee K, Huang H, Tsai Y, Wu Y, Kuo T, et al. HNF-4? determines hepatic differentiation of human mesenchymal stem cells from bone marrow. World J Gastroenterol. 2010;16:5092-103 pubmed..Overexpression of HNF-4? improves the hepatic differentiation of human MSCs from bone marrow and is a simple way of providing better cell sources for clinical applications. ..
- Marcil V, Seidman E, Sinnett D, Boudreau F, Gendron F, Beaulieu J, et al. Modification in oxidative stress, inflammation, and lipoprotein assembly in response to hepatocyte nuclear factor 4alpha knockdown in intestinal epithelial cells. J Biol Chem. 2010;285:40448-60 pubmed publisherb>Hepatocyte nuclear factor 4? (HNF4?) is a nuclear transcription factor mainly expressed in the liver, intestine, kidney, and pancreas...
- Hwang Verslues W, Sladek F. HNF4?--role in drug metabolism and potential drug target?. Curr Opin Pharmacol. 2010;10:698-705 pubmed publisherb>Hepatocyte nuclear factor 4? (HNF4?) is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors...
- Dankel S, Hoang T, Flågeng M, Sagen J, Mellgren G. cAMP-mediated regulation of HNF-4alpha depends on the level of coactivator PGC-1alpha. Biochim Biophys Acta. 2010;1803:1013-9 pubmed publisher..In conclusion, our results suggest that the level of PGC-1alpha determines whether the cAMP/PKA-pathway overall stimulates or inhibits HNF-4alpha transcriptional activation. ..
- Niehof M, Borlak J. Expression of HNF4alpha in the human and rat choroid plexus: implications for drug transport across the blood-cerebrospinal-fluid (CSF) barrier. BMC Mol Biol. 2009;10:68 pubmed publisher..Our study evidences activity of HNF4alpha in human and rat choroid plexus. This transcription factor targets DMEs and drug transporters and may well determine availability of drugs at the blood-CSF barrier. ..
- Johansson S, Raeder H, Eide S, Midthjell K, Hveem K, Søvik O, et al. Studies in 3,523 Norwegians and meta-analysis in 11,571 subjects indicate that variants in the hepatocyte nuclear factor 4 alpha (HNF4A) P2 region are associated with type 2 diabetes in Scandinavians. Diabetes. 2007;56:3112-7 pubmedRecent publications have found an association between common variants near the hepatocyte nuclear factor 4 alpha (HNF4A) P2 promoter and type 2 diabetes in some populations but not in others, and the role for HNF4A in type 2 diabetes has ..
- Lu P, Liu J, Melikishvili M, Fried M, Chi Y. Crystallization of hepatocyte nuclear factor 4 alpha (HNF4 alpha) in complex with the HNF1 alpha promoter element. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008;64:313-7 pubmed publisher..A molecular-replacement solution has been obtained and structure refinement is in progress. This structure and the binding studies will provide the groundwork for detailed functional and biochemical studies of the MODY mutants. ..
- Lu H, Gonzalez F, Klaassen C. Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha. Toxicol Sci. 2010;118:380-90 pubmed publisherb>Hepatocyte nuclear factor 4 alpha (HNF4a) is a liver-enriched master regulator of liver function. HNF4a is important in regulating hepatic expression of certain cytochrome P450s...
- Kanazawa T, Konno A, Hashimoto Y, Kon Y. Expression of hepatocyte nuclear factor 4alpha in developing mice. Anat Histol Embryol. 2009;38:34-41 pubmed publisher..Immunohistochemistry for HNF4alpha and HNF1alpha revealed that both factors involved the same network of transcription factors, giving the impression that HNF4alpha was upstream of HNF1alpha. ..
- Wang S, Yeh S, Lin W, Yeh K, Yuan Q, Xia N, et al. Estrogen receptor ? represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4?. Gastroenterology. 2012;142:989-998.e4 pubmed publisher..These findings might account for the lower viral load and reduced incidence of liver cancer in HBV-infected women than men. ..
- Bolotin E, Liao H, Ta T, Yang C, Hwang Verslues W, Evans J, et al. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays. Hepatology. 2010;51:642-53 pubmed publisherb>Hepatocyte nuclear factor 4 alpha (HNF4alpha), a member of the nuclear receptor superfamily, is essential for liver function and is linked to several diseases including diabetes, hemophilia, atherosclerosis, and hepatitis...
- Takagi S, Nakajima M, Kida K, Yamaura Y, Fukami T, Yokoi T. MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle. J Biol Chem. 2010;285:4415-22 pubmed publisher..In conclusion, we found that human HNF4alpha was down-regulated by miR-24 and miR-34a, the expression of which are regulated by cellular stress, affecting the metabolism and cellular biology. ..
- Cattin A, Le Beyec J, Barreau F, Saint Just S, Houllier A, Gonzalez F, et al. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Mol Cell Biol. 2009;29:6294-308 pubmed publisher..This study indicates that HNF-4alpha regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor. ..
- Huang J, Levitsky L, Rhoads D. Novel P2 promoter-derived HNF4alpha isoforms with different N-terminus generated by alternate exon insertion. Exp Cell Res. 2009;315:1200-11 pubmed..We recommend inclusion of exon 1E and nearby DNA sequences in screening for HNF4alpha mutations and polymorphisms in genetic analyses of MODY1 and T2DM. ..
- Chellappa K, Jankova L, Schnabl J, Pan S, Brelivet Y, Fung C, et al. Src tyrosine kinase phosphorylation of nuclear receptor HNF4? correlates with isoform-specific loss of HNF4? in human colon cancer. Proc Natl Acad Sci U S A. 2012;109:2302-7 pubmed publisher..The nuclear receptor hepatocyte nuclear factor 4? (HNF4?) has just recently been implicated in colon cancer but its role is poorly defined...
- Hanse E, Mashek D, Becker J, Solmonson A, Mullany L, Mashek M, et al. Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4?. Cell Cycle. 2012;11:2681-90 pubmed publisher..Because changes in ChREBP activity could not fully explain the effect of cyclin D1, we examined hepatocyte nuclear factor 4? (HNF4?), which regulates numerous differentiated functions in the liver including lipid metabolism...
- Babeu J, Boudreau F. Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks. World J Gastroenterol. 2014;20:22-30 pubmed publisherb>Hepatocyte nuclear factor 4-alpha (HNF4-?) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells...
- Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature. 2011;475:390-3 pubmed publisher..The generation of iHep cells may provide insights into the molecular nature of hepatocyte differentiation and potential therapies for liver diseases. ..
- Verzi M, Shin H, He H, Sulahian R, Meyer C, Montgomery R, et al. Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2. Dev Cell. 2010;19:713-26 pubmed publisher..These results reveal dynamic, context-specific functions and mechanisms of a prominent transcriptional regulator within a cell lineage. ..
- Daigo K, Kawamura T, Ohta Y, Ohashi R, Katayose S, Tanaka T, et al. Proteomic analysis of native hepatocyte nuclear factor-4? (HNF4?) isoforms, phosphorylation status, and interactive cofactors. J Biol Chem. 2011;286:674-86 pubmed publisher..This suggests that the analysis of the distinctive stoichiometric balance of native HNF4? and its cofactor complexes described here are important for an accurate understanding of transcriptional regulation. ..
- Zhang Y, Soto J, Park K, Viswanath G, Kuwada S, Abel E, et al. Nuclear receptor SHP, a death receptor that targets mitochondria, induces apoptosis and inhibits tumor growth. Mol Cell Biol. 2010;30:1341-56 pubmed publisher..Thus, SHP regulates a mechanism by which apoptotic signals can mediate local control of mitochondrial function and apoptosis, which in turn may limit tumorigenesis. ..
- Ganjam G, Dimova E, Unterman T, Kietzmann T. FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol. J Biol Chem. 2009;284:30783-97 pubmed publisher..These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol. ..
- Benahmed F, Gross I, Gaunt S, Beck F, Jehan F, Domon Dell C, et al. Multiple regulatory regions control the complex expression pattern of the mouse Cdx2 homeobox gene. Gastroenterology. 2008;135:1238-1247, 1247.e1-3 pubmed publisher..Cooperation between HNF4alpha, GATA6, beta-catenin, and Tcf4 contributes to the intestine-specific expression of Cdx2. ..
- Gonzalez F. Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet. 2008;23:2-7 pubmed..The ability of HNF4alpha to be regulated offers hope that it could be a drug target. ..
- Fajans S, Bell G. Macrosomia and neonatal hypoglycaemia in RW pedigree subjects with a mutation (Q268X) in the gene encoding hepatocyte nuclear factor 4alpha (HNF4A). Diabetologia. 2007;50:2600-1 pubmed
- Hwang Verslues W, Sladek F. Nuclear receptor hepatocyte nuclear factor 4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter. Mol Endocrinol. 2008;22:78-90 pubmed..These results suggest a general model by which a differentiation factor (HNF4alpha1) and a proliferation factor (c-Myc) may compete for control of genes involved in cell proliferation and differentiation. ..
- Taghavi S, Fatemi S, Rafatpanah H, Ganjali R, Tavakolafshari J, Valizadeh N. Mutations in the coding regions of the hepatocyte nuclear factor 4 alpha in Iranian families with maturity onset diabetes of the young. Cardiovasc Diabetol. 2009;8:63 pubmed publisher..In the family members, 3 subjects with the age of <or=25 years old carried this mutation. Therefore, holding this mutation in this range of age could be a predisposing factor for developing diabetes in future. ..
- Boj S, Servitja J, Martin D, Rios M, Talianidis I, Guigo R, et al. Functional targets of the monogenic diabetes transcription factors HNF-1alpha and HNF-4alpha are highly conserved between mice and humans. Diabetes. 2009;58:1245-53 pubmed publisher..Despite evolutionary changes in binding, essential direct transcriptional functions of HNF-1alpha and -4alpha are largely conserved between mice and humans. ..