Hepatocyte nuclear factor 4

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Hepatocyte nuclear factor 4 alpha
Alt. symbolsTCF14, MODY, MODY1
Other data
LocusChr. 20 q12-20q13.1
Hepatocyte nuclear factor 4 gamma
Other data
LocusChr. 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]


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.


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


  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 V, 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