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Hepatocyte nuclear factor 4 alpha
Identifiers
Symbol HNF4A
Alt. symbols TCF14, MODY, MODY1
Entrez 3172
HUGO 5024
OMIM 600281
PDB 1M7W (RCSB PDB PDBe PDBj)
RefSeq NM_001030004
UniProt P41235
Other data
Locus Chr. 20 q12-20q13.1
Hepatocyte nuclear factor 4 gamma
Identifiers
Symbol HNF4G
Entrez 3174
HUGO 5026
OMIM 605966
PDB 1LV2 (RCSB PDB PDBe PDBj)
RefSeq NM_004133
UniProt Q14541
Other data
Locus Chr. 8 q21-q22

HNF4 (Hepatocyte Nuclear Factor 4) is a nuclear receptor protein mostly expressed in the liver, gut, kidney, and pancreatic beta cells that is critical for liver development. In humans, there are two isoforms of HNF4, HNF4α and HNF4γ, encoded by two separate genes HNF4A and HNF4G respectively.[1]

Ligands[edit]

HNF4 was originally classified as an orphan receptor that exhibits constitutive transactivation activity apparently by being continuously bound to a variety of fatty acids.[2][3] The existence of a ligand for HNF4 has been somewhat controversial, but linoleic acid (LA) has been identified as the endogenous ligand of native HNF4 expressed in mouse liver; the binding of LA to HNF4 is reversible.[4]

The ligand binding domain of HNF4, as with other nuclear receptors, adopts a canonical alpha helical sandwich fold[5][6] and interacts with co-activator proteins.[7]

HNF4 binds to the consensus sequence AGGTCAaAGGTCA in order to activate transcription.

Pathology[edit]

Mutations in the HNF4A gene have been linked to maturity onset diabetes of the young 1 (MODY1).[8]

This seems to be caused by HNF4-a's [1] role in the synthesis of SHBG, which is known to be severely diminished in patients with insulin-resistance.

See also[edit]

References[edit]

  1. ^ Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (1994). "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver". Gene 147 (2): 269–72. doi:10.1016/0378-1119(94)90079-5. PMID 7926813. 
  2. ^ Sladek F (August 2002). "Desperately seeking...something". Mol. Cell 10 (2): 219–21. doi:10.1016/S1097-2765(02)00605-6. PMID 12191466. 
  3. ^ Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O (November 2005). "Fatty acid regulation of hepatic gene transcription". J. Nutr. 135 (11): 2503–6. PMID 16251601. 
  4. ^ Yuan X, Ta TC, Lin M, Evans JR, Dong Y, Bolotin E, Sherman MA, Forman BM, Sladek FM (2009). Laudet, Vincent, ed. "Identification of an endogenous ligand bound to a native orphan nuclear receptor". PLoS ONE 4 (5): e5609. doi:10.1371/journal.pone.0005609. PMC 2680617. PMID 19440305. 
  5. ^ Wisely GB, Miller AB, Davis RG, Thornquest AD, Johnson R, Spitzer T, Sefler A, Shearer B, Moore JT, Miller AB, Willson TM, Williams SP (September 2002). "Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids". Structure 10 (9): 1225–34. doi:10.1016/S0969-2126(02)00829-8. PMID 12220494. 
  6. ^ Dhe-Paganon S, Duda K, Iwamoto M, Chi YI, Shoelson SE (October 2002). "Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand". J. Biol. Chem. 277 (41): 37973–6. doi:10.1074/jbc.C200420200. PMID 12193589. 
  7. ^ Duda K, Chi YI, Shoelson SE (May 2004). "Structural basis for HNF-4alpha activation by ligand and coactivator binding". J. Biol. Chem. 279 (22): 23311–6. doi:10.1074/jbc.M400864200. PMID 14982928. 
  8. ^ Fajans SS, Bell GI, Polonsky KS (2001). "Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young". N Engl J Med 345 (13): 971–80. doi:10.1056/NEJMra002168. PMID 11575290. 

External links[edit]


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