Receptor nomenclature NR2A1
Receptor code 4.10.1:OR:2:A1
Other names HNF-4, MODY1, TCF14
Molecular information Hs: 465aa, P41235, chr. 20q131,2
Rn: 465aa, P22449, chr. 3q423,4
Mm: 465aa, P49698, chr. 2 H35,6
DNA binding
   Structure Homodimer
   HRE core sequence AGGTCA n AGGTCA (DR-1, DR-2)4,7
Partners HIF (physical, functional): transactivation810; HNF-1A (physical, functional): transactivation1113; COUP-TFI, COUP-TFII (functional): transactivation and competition for DNA binding1416; SHP (physical, functional): transactivation17,18; SMADs (physical, functional): transactivation19,20
Corepressors NCOR228
Biologically important isoforms HNF-4α1 {Hs, Mm, Rn}: main isoform1,4,5; HNF-4α2 (variant B){Hs, Mm, Rn}: contains an additional 10 amino acids in the F domain and is the most prominent form in the liver and kidney1,5,21; HNF-4α3 (variant C) {Hs, Mm}: displays reduced transcriptional activity and liver expression compared with isoforms 1 and 229; HNF-4α4 {Hs, Mm}: this variant has an insertion in the AF-1 of HNF-4α130; HNF-4α7 and HNF-4α8 {Hs, Mm, Rn}: transcribed from a different promoter and have a different N terminus from the isoforms above but the same F domain as HNF-4α1 and HNF-4α23134
Tissue distribution Developmental: primary endoderm, liver, kidney, pancreas, stomach, intestine; adult: HNFα-1 and -2–liver (hepatocytes), kidney, small intestine and colon but not in the pancreas; HNFα-3 and -4–liver; HNFα-7–pancreas, adult liver, small intestine, colon, stomach but not in the liver {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]4,3537
Functional assays Measurement of receptor activity using CAT and luciferase reporter genes in HeLa, HepG2, Hep3B, Saos2, Caco-2, and HEK 293 cells {Hs}4,28,38; ectopic overexpression of HNF-4α in fibroblasts induces a mesenchymal-to-epithelial transition, indicating that HNF-4α is a dominant regulator of the epithelial phenotype {Mm}39
Main target genes Activated: ApoC3 {Hs, Mm, Rn},4,40,41 ApoB {Hs},41,42 HNF1A {Hs, Mm, Rn},41,43,44 PEPCK {Hs, Mm, Rn},41,45 CYP3A4 {Hs}34,46,47
Mutant phenotype Targeted disruption of the HNF-4α gene results in embryonic lethality; the embryos initiate but do not complete gastrulation in the absence of HNF-4α {Mm} [knockout]48,49; adult mice lacking hepatic HNF-4α expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations {Mm} [knockout]39,50,51; mice lacking HNF-4α in pancreatic β cells have hyperinsulinemia and, paradoxically, impaired glucose tolerance, as well as impaired glucose-stimulated insulin secretion and dysfunction of the KATP channel activity {Mm} [conditional knockout]52,53
Human disease Early-onset type 2 diabetes: due to the three SNPs (Asp126→Tyr, Asp126→His, Arg154→Gln)54; late-onset type 2 diabetes: due to missense mutations in the LBD and F domain and 13 SNPs in the P2 promoter5558; MODY1: caused by mutations in several different human populations affecting either the DBD or LBD32,5963; factor VII deficiency: caused by mutations in the HNF-4α-binding site in the blood coagulation factor VII gene64; hemophilia B Leyden: caused by mutations in the HNF-4α-binding site in the blood coagulation factor IX gene6567
  • aa, amino acids; chr., chromosome; HRE, hormone response element; HIF, hypoxia-inducing factor; CREBBP, cAMP response element-binding protein binding protein; PPARGC, PPAR coactivator gene; PPARBP, PPAR binding protein; SNP, single-nucleotide polymorphism; MODY1, maturity-onset diabetes of the young type 1; CAT, chloroamphenicol acetyl transferase; PEPCK, phosphoenolpyruvate carboxykinase

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