HCF-1 Regulates De Novo Lipogenesis through a Nutrient-Sensitive Complex with ChREBP

Mol Cell. 2019 Jul 25;75(2):357-371.e7. doi: 10.1016/j.molcel.2019.05.019. Epub 2019 Jun 18.


Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched in liver biopsies of nonalcoholic steatohepatitis (NASH) patients. Biochemical and genetic studies show that HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP and subsequent recruitment of OGT, ChREBP O-GlcNAcylation, and activation. The HCF-1:ChREBP complex resides at lipogenic gene promoters, where HCF-1 regulates H3K4 trimethylation to prime recruitment of the Jumonji C domain-containing histone demethylase PHF2 for epigenetic activation of these promoters. Overall, these findings define HCF-1's interaction with ChREBP as a previously unappreciated mechanism whereby glucose signals are both relayed to ChREBP and transmitted for epigenetic regulation of lipogenic genes.

Keywords: ChREBP; H3K4 trimethylation; HCF-1; NASH; O-GlcNAcylation; OGT; PHF2; de novo lipogenesis; glucose; hexosamine biosynthesis pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Carbohydrates / genetics
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Glucose / metabolism
  • Hexosamines / genetics
  • Hexosamines / metabolism
  • Homeodomain Proteins / genetics*
  • Host Cell Factor C1 / genetics*
  • Humans
  • Lipogenesis / genetics*
  • Liver / metabolism
  • Mice
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Promoter Regions, Genetic / genetics
  • Protein Interaction Maps / genetics


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carbohydrates
  • HCFC1 protein, human
  • Hexosamines
  • Homeodomain Proteins
  • Host Cell Factor C1
  • MLXIPL protein, human
  • PHF2 protein, human
  • Glucose