Hepatocyte nuclear factor (HNFa) is the master regulator of hepatic differentiation because it regulates over 60% of genes involved in specific functions of the liver. The functional gene plays a major role in the development of liver, kidney, and intestine. Continue to read to know more about the significance of this nuclear receptor on human health.

What is Hepatocyte Nuclear Factor?


Hepatocyte Nuclear factor alpha (HNFa) also known as NR2A1 is a nuclear receptor in humans and is encoded by the HNF4A gene [1].

The regulation of a gene by HNFa in rodents depends on numerous diverse factors such as the developmental stage, the type of tissue, and the environmental conditions [2].

Effects of Hepatocyte Nuclear Factor (HNFa) on Health

1) Promotes Stomach Cell Growth

Hepatocyte Nuclear Factor (HNFa) plays a key role in stimulating the development of the cells in the stomach as illustrated by a study done on knockout mice [3].

2) May Regulate Blood Sugar

In the Chinese interplay among Hepatocyte Nuclear Factor (HNFa) and PPARG (Peroxisome proliferator-activated receptor gamma), genes could contribute to the body’s ability to control blood sugar as evidenced by the results after a sugar (glucose) challenge test [4].

Mutation of the Hepatocyte Nuclear Factor (HNFa) gene leads to maturity-onset diabetes of the young (MODY), but in a study examining white people with type 2 diabetes mellitus, there was negligible risk identified with the rare variants of this gene [5].

3) Plays a Key Role in Liver Function

Hepatocyte Nuclear Factor (HNFa) protein manages human metabolic enzymes in the liver by modifying other genes [6].

As proteins that work as hormone sensors PPARa (Peroxisome proliferator-activated receptor alpha) and HNFa are required for the regulation of a number of important metabolic functions within the liver [7].

HNFa increased the production of sugar in old rat liver cells by stimulating regulatory enzymes [8].

4) Controls the Spread of Kidney Cancer

Declining HNFa gene levels have been implicated in kidney cancer and HNFa is in control of how these cells multiply by regulating fourteen different genes involved in the start of cancer development [9].

5) Encourages Healthy Drug Metabolism

HNFa in human liver cells directs the activation of proteins found within cells (PXR and CAR) which helps foster the digestion of drugs [10].

The toxic byproducts of acetaminophen digestion trigger HNFa and other receptors (PXR and CAR); microRNA (miR-561) treatments could help in treating liver injuries related to this medication [10].

Negative Effects Associated With Hepatocyte Nuclear Factor (HNFa)

1) Mutations Could be Connected to a Risk for Diabetes

A mutation of HNFa called the delta 7 promoter deletion suggests that mutations such as these may suggest some predisposition for diabetes [11].

Physical activity shaped the consequences of several HNFa forms on the chances of developing type 2 diabetes mellitus in white families [12].

The risk of developing type 2 diabetes mellitus is higher for carriers of the P2 variant of HNF4a as shown by the increased insulin resistance displayed by a genetics study of healthy subjects [13].

2) Receptor Decreases Fat Breakdown

A study done on the human liver cell line has shown how the HNFa receptor is involved in decreasing the production of proteins that play a role in the metabolism of fats [14].

3) Mutations Cause Decreased Liver Activity

In patients with MODY1 (HNF4a upstream regulator of HNF1a gene mutations) the decrease of activity in HNFa controlled liver enzymes may explain lowered levels of fats [6].

4) Is Suppressed by Liver Cancer

Liver cancer inactivates the HNFa protein in mice; gankyrin is activated by liver cancer and it is this protein that blocks the activity of tumor-suppressing proteins like HNFa [15].

5) Activity is Connected to Kidney Disease

Alteration of HNFa in animal studies has been associated with diabetic kidney disease and has potential in the future development of a treatment for human patients [16].

The HNFa gene does not appear to be directly related to the diagnosis of diabetic kidney disease in whites according to a study of genetic mutations [11].

6) May Advance Cancer

In human kidney cancer, the HNFa pathway has been tied to the spread of cancerous tissue [17].


  • These data reveal striking developmental and tissue-specific variation in expression of HNF4-alpha and indicate that this can be influenced by environmental factors (such as exposure to glucocorticoid excess), with potential pathophysiological consequences [2].
  • Furthermore, Hnf4a conditional knockout mice fail to induce Cldn23 during colonocyte differentiation [3].
  • In conclusion, we report a comprehensive screen of colonic claudin gene expression and discover spatiotemporal Hopx/Klf4 and Tcf7l2/Hnf4a signaling as stimulators of colonic epithelial barrier differentiation [3].
  • Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), an uncommon, autosomal dominant, non-insulin dependent form of diabetes [5].
  • We conclude there is little evidence to suggest that HNF4α variants contribute significantly to the risk of T2DM in the general population, but a modest contribution cannot be excluded [5].
  • Functional analysis of the Delta 7 promoter deletion suggests, however, that promoter mutations in otherwise normal genes could contribute to diabetes susceptibility [11].
  • Our finding, therefore suggests that the effect of HNF4A polymorphisms on the risk of T2DM is influenced by PA [12].
  • These results indicate that the associations of HNF4A rs1885088 with glucose tolerance and rs745975 with insulin secretion are modulated by PA [12].
  • And we also observed that ABCC8 as well as, the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion [4].
  • In conclusion, subjects with HNF4 alpha P2 variants and haplotypes have been shown to have higher insulin resistance and are therefore at a higher risk for developing type 2 diabetes mellitus [13].
  • These results suggest that nuclear receptors HNF4alpha, PPARalpha, and LXRs are involved in the TNF-alpha-mediated downregulation of human apoA-I gene expression and apoA-I protein secretion in HepG2 cells [14].
  • We identified HNF4alpha as an important regulator of the hepatocyte-specific expression of the human ACAT2 promoter [6].
  • The current data indicate the requirement of PPARα and HNF4α for regulation in the liver of peroxisomal and mitochondrial fatty acid β-oxidation, cholesterol and bile acid metabolism, lipoprotein metabolism and consequently the prevention of liver steatosis [7].
  • This study suggests that the mild hypoxic conditions in response to aging-dependent hepatic structural changes may contribute to the induction of the gluconeogenic enzyme PEPCK through HNF4α protein stabilization [8].
  • Our results suggest that the lower levels of esterified cholesterol in VLDL- and LDL-particles in patients with MODY1 may at least in part be attributable to lower ACAT2 activity in these patients [6].
  • One of the early events in the development of liver cancer is neutralization of the tumor suppressor proteins Rb, p53, HNF4α and C/EBPα [15].
  • Gankyrin is a protein which is activated in liver cancer and which causes degradation or elimination of activities of five tumor suppressor proteins; Rb, p53, C/EBPα HNF4α, and p16. [15].
  • Taken collectively, results obtained from animal studies could be translated to human diabetic nephropathy; there is evidence for a common regulation of HNF 4 alpha and TRPC1 in human and rat kidney pathologies [16].
  • Therefore, we postulate that HNF4 alpha orchestrates, at least, these 14 genes to regulate cell proliferation in HEK293 cells and that down-regulation of HNF4 alpha could contribute to the progression of kidney cancer [9].
  • Analysis of the HNF4 alpha gene revealed two possible mutations in 182 diabetic patients which suggest that the HNF4 alpha gene does not make a large contribution to diabetes susceptibility in the general population of Caucasian diabetic nephropathic patients [11].
  • We, therefore, speculate that disruption of the HNF4 alpha/HNF1 alpha pathway of kidney-specific gene expression might be an important molecular mechanism in renal cell carcinogenesis [17].
  • These results indicate that HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4 in hepatocytes [10].
  • Our study demonstrated that APAP induces suppression of miR-561-mediated DAX-1 expression and induces the transactivation of HNF4α, and subsequent transactivation of PXR/CAR, which should ultimately cause CYP3A4/5 activation that converts APAP to toxic NAPQI and contributes to APAP-induced liver injury [10].

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