Increased expression of enzymes of triglyceride synthesis is essential for the development of hepatic steatosis

Cell Rep. 2013 Mar 28;3(3):831-43. doi: 10.1016/j.celrep.2013.02.009. Epub 2013 Mar 14.


Molecular mechanisms underpinning nonalcoholic fatty liver disease (NAFLD) are not well understood. The earliest step of NAFLD is hepatic steatosis, which is one of the main characteristics of aging liver. Here, we present a molecular scenario of age-related liver steatosis. We show that C/EBPα-S193D knockin mice have age-associated epigenetic changes and develop hepatic steatosis at 2 months of age. The underlying mechanism of the hepatic steatosis in old wild-type (WT) mice and in young S193D mice includes increased amounts of tripartite p300-C/EBPα/β complexes that activate promoters of five genes that drive triglyceride synthesis. Knockdown of p300 in old WT mice inhibits hepatic steatosis. Indeed, transgenic mice expressing dominant-negative p300 have fewer C/EBPα/β-p300 complexes and do not develop age-dependent hepatic steatosis. Notably, the p300-C/EBPα/β pathway is activated in the livers of patients with NAFLD. Thus, our results show that p300 and C/EBP proteins are essential participants in hepatic steatosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Diacylglycerol O-Acyltransferase / genetics
  • Diacylglycerol O-Acyltransferase / metabolism*
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Epigenesis, Genetic
  • Fatty Liver / enzymology
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Humans
  • Mice
  • Mutation
  • Promoter Regions, Genetic
  • Transcription, Genetic*
  • Triglycerides / biosynthesis*
  • Up-Regulation*


  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Protein-beta
  • Triglycerides
  • Diacylglycerol O-Acyltransferase
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse