Hnf4a

HNF4A, or hepatocyte nuclear factor 4 alpha, is a nuclear receptor transcription factor encoded by the HNF4A gene. It belongs to the nuclear receptor superfamily and regulates gene expression by binding DNA as a homodimer to hepatocyte nuclear factor 4 response elements in promoters and enhancers of liver- and pancreas-enriched genes.

The HNF4A gene produces two major isoforms via alternative promoter usage (P1 and P2), generating proteins with different N-terminal regions. P1-derived isoforms predominate in liver and pancreas, while P2-derived isoforms are enriched in the intestine.

HNF4A is essential for hepatocyte differentiation and adult liver function; knockout models show impaired hepatic development and disrupted metabolic gene expression. It also influences pancreatic beta-cell development and insulin secretion, linking it to glucose homeostasis.

The protein regulates genes involved in glucose and lipid metabolism, plasma protein synthesis (including albumin and apolipoproteins), and other liver-specific functions. It is generally regarded as constitutively active with no clearly defined endogenous ligand, though fatty-acid–like molecules have been proposed as modulators in some studies.

Clinically, heterozygous mutations in HNF4A cause MODY1 (maturity-onset diabetes of the young type 1), an autosomal dominant form of diabetes due to impaired insulin secretion. Some HNF4A mutations can cause neonatal hyperinsulinemic hypoglycemia with later progression to diabetes. The gene is a focus of research in metabolic disease and cancer biology, and its activity is modulated by interactions with other transcription factors and coactivators such as HNF1A, C/EBPα, and PGC-1α.