Hepatocyte Nuclear Factors (HNFs), though originally discovered in the liver, are distinct transcription factors belonging to several families and involved in a wide variety of biological pathways. To date, several different HNFs have been described:  HNF1α and β, HNF3α, β and γ, HNF4α and HNF6α and β. Although all are important in liver development and function, HNFs are also found in other tissues such as the kidney, spleen, thymus and pancreas.

HNF1 is a member of the homeodomain family. The N-terminus contains a dimerization domain allowing for homo- or heterodimerization. HNF1 plays a crucial role in liver development during embryogenesis and metabolism homeostasis in the adult. It helps regulate such genes as glucose-cotransporter-2 in the kidney, phenylalanine hydroxylase (PAH) in the liver and insulin, L-pyruvate kinase and aldolase B in pancreatic B cells. HNF3α, β and γ are members of the winged-helix/forkhead DNA binding domain family. They are found in the liver, pancreas, intestine and lung. HNF3 target genes include albumin, Apo B, transferrin, insulin-like growth factor binding protein 1, aldolase B and complement protein C. HNF4 is a member of the steroid hormone receptor superfamily, similar to RXR. It is found in the liver, kidney, intestine and pancreas. It regulates genes such as apoA-I, apoA-II and apoB for lipid metabolism, insulin, pyruvate kinase and dehydrogenase for protein metabolism, and factors VII, IX, X and fibrinogen for blood coagulation. It also regulates the expression of HNF1. HNF6 is the prototype of the novel ONECUT class of cut-homeoproteins, characterized by the presence of a single cut domain. It is present in the liver, brain, spleen, pancreas and testis. It controls genes coding for 6-phosphofructo-2-kinase (involved in glucose metabolism), CYP2C12 (involved in steroid metabolism), transthyretin (involved in plasma transport) and protein C (controls blood coagulation). HNF6 also regulates the expression of HNF3β and 4.

In addition, mutations in HNF genes have been shown to lead to Maturity Onset Diabetes of the Young (MODY), which is characterized by an autosomal dominant inheritance, an early age onset and abnormal pancreatic B-cell function. MODY1 represents mutations in HNF4α, MODY3 represents mutations in HNF1β and MODY5 represents mutations in HNF1β. It has also been proposed that HNF3β is involved in late-onset type II diabetes, but there is no clear evidence to support this theory. The most common form is MODY3, accounting for about 60% of cases. In all forms of MODY, insulin levels are affected by defective secretions of pancreatic B-cells.