The molecular functions of hepatocyte nuclear factors - In and beyond the liver

J Hepatol. 2018 May;68(5):1033-1048. doi: 10.1016/j.jhep.2017.11.026. Epub 2017 Nov 24.


The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions.

Keywords: Development; Disease; Hepatocyte nuclear factor; Liver; MODY; Regulatory network; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Hepatocyte Nuclear Factors / chemistry
  • Hepatocyte Nuclear Factors / genetics
  • Hepatocyte Nuclear Factors / metabolism*
  • Humans
  • Kidney / metabolism
  • Liver / growth & development
  • Liver / metabolism*
  • Metabolic Networks and Pathways
  • Mutation
  • Pancreas / metabolism
  • Tissue Distribution


  • Hepatocyte Nuclear Factors