HNF4

Hepatocyte nuclear factor 4 (HNF4) is a nuclear receptor transcription factor that plays a central role in development and metabolic regulation of the liver, kidney, and intestine. In humans, the best-characterized members are HNF4A (hepatocyte nuclear factor 4 alpha) and HNF4G (hepatocyte nuclear factor 4 gamma), encoded by the HNF4A and HNF4G genes. HNF4A is the predominant isoform in the adult liver and is essential for maintaining hepatic and intestinal gene expression programs.

Structure and mechanism: HNF4 proteins belong to the nuclear receptor superfamily and function as key transcriptional regulators. They contain an N-terminal transactivation domain, a central DNA-binding domain with two zinc fingers, and a ligand-binding domain. They bind DNA as obligate homodimers to direct-repeat DR1-type elements. Although historically viewed as constitutively active, receptor activity can be modulated by fatty acids and other lipids that bind to the ligand-binding domain, as well as by interactions with coactivators such as PGC-1α and SRC-1. HNF4A is predominantly a homodimer, and RXR heterodimerization is not required for DNA binding.

Function and expression: HNF4 regulates a large network of liver- and intestine-expressed genes, especially those involved in glucose and lipid metabolism and plasma protein synthesis. It cooperates with other transcription factors, including HNF1 and C/EBPs, to coordinate metabolic gene expression programs.

Clinical relevance: Mutations in HNF4A cause MODY1 (maturity-onset diabetes of the young type 1), a monogenic form of diabetes. Genetic variation at HNF4A has also been linked to metabolic trait differences in population studies, though effects are context-dependent. Animal models lacking Hnf4a in liver or intestine show developmental and metabolic defects, underscoring its essential role.