Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (nuclear receptor subfamily 2, group A, member 1) is a nuclear receptor that in humans is encoded by the HNF4Agene.[5][6]
Function
HNF-4α is a nuclear transcription factor that binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor that regulates the expression of several hepatic genes. This gene plays a role in development of the liver, kidney, and intestines. Alternative splicing of this gene results in multiple transcript variants.[7]
HNF4A is required for the PXR and CAR-mediated transcriptional activation of CYP3A4.[8] Genetic mutations in the HNF4A gene can influence the activity of HNF4α's downstream proteins such as CYP2D6, in vitro and in vivo.[9][10]
The alkaloid berberine upregulates HNF4A expression.[11]
This gene plays a pivotal role in the expression and synthesis of SHBG, an important glycoprotein made primarily in the liver,[12] which in addition to lowering insulin-resistance also reduces levels of free Estrogen as-well as prolonging the half-life of testosterone.[citation needed]
Function of HNF4A gene can be effectively examined by siRNA knockdown based on an independent validation.[13]
Clinical significance
Mutations in the HNF4A gene are associated with a form of diabetes called maturity onset diabetes of the young (MODY),[14] specifically MODY 1. At least 56 disease-causing mutations in this gene have been discovered.[15]
Increased amplification of hepatocyte nuclear factor 4 alpha has been observed in colorectal cancer.[16]
It has also associations with the appearance of Fanconi syndrome phenotypes which occurs due to a missense mutation of the gene.[17]
Interactions
Hepatocyte nuclear factor 4 alpha has been shown to interact with:
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (Sep 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. PMID7926813.
^Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK (Feb 1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Human Genetics. 99 (2): 233–6. doi:10.1007/s004390050345. PMID9048927. S2CID10943721.
^Jiang F, Yeo CW, Lee SS, Oh MK, Ghim JL, Shon JH, Kim HS, Kim EY, Kim DH, Shin JG (2013). "Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals". Pharmacogenetics and Genomics. 23 (3): 175–9. doi:10.1097/FPC.0b013e32835de25e. PMID23292115. S2CID19230792.
^Yamagata K (2014). "Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY)". Vitamins and Hormones. 95: 407–23. doi:10.1016/B978-0-12-800174-5.00016-8. PMID24559927.
^Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC (Aug 2003). "Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis". Oncogene. 22 (36): 5602–13. doi:10.1038/sj.onc.1206802. PMID12944908. S2CID9301471.
^Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, Fukamizu A (Dec 1997). "Functional association between CBP and HNF4 in trans-activation". Biochemical and Biophysical Research Communications. 241 (3): 664–9. doi:10.1006/bbrc.1997.7871. PMID9434765.
Winter WE, Nakamura M, House DV (Dec 1999). "Monogenic diabetes mellitus in youth. The MODY syndromes". Endocrinology and Metabolism Clinics of North America. 28 (4): 765–85. doi:10.1016/S0889-8529(05)70101-8. PMID10609119.
Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (Sep 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. PMID7926813.
Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI (Dec 1996). "Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1)". Nature. 384 (6608): 458–60. Bibcode:1996Natur.384..458Y. doi:10.1038/384458a0. hdl:2027.42/62605. PMID8945471. S2CID4253951.
Kritis AA, Argyrokastritis A, Moschonas NK, Power S, Katrakili N, Zannis VI, Cereghini S, Talianidis I (Sep 1996). "Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4". Gene. 173 (2): 275–80. doi:10.1016/0378-1119(96)00183-7. PMID8964514.
Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK (Feb 1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Human Genetics. 99 (2): 233–6. doi:10.1007/s004390050345. PMID9048927. S2CID10943721.
Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI (Oct 1997). "Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY". Diabetes. 46 (10): 1652–7. doi:10.2337/diabetes.46.10.1652. PMID9313765.
