CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis

Hepatology. 2007 May;45(5):1108-17. doi: 10.1002/hep.21614.


Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, inflammation, and oxidative stress. To investigate whether the transcription factor CCAAT/Enhancer binding protein (C/EBPbeta) is involved in the development of NASH, C57BL/6J wild-type (WT) or C/EBPbeta knockout (C/EBPbeta-/-) mice were fed either a methionine and choline deficient (MCD) diet or standard chow. These WT mice fed a MCD diet for 4 weeks showed a 2- to 3-fold increase in liver C/EBPbeta messenger RNA and protein, along with increased expression of lipogenic genes peroxisome proliferators-activated receptor gamma and Fas. WT mice also showed increased levels of the endoplasmic reticulum stress pathway proteins phosphorylated eukaryotic translation initiation factor alpha, phosphorylated pancreatic endoplasmic reticulum kinase, and C/EBP homologous protein, along with inflammatory markers phosphorylated nuclear factor kappaB and phosphorylated C-jun N-terminal kinase compared to chow-fed controls. Cytochrome P450 2E1 protein and acetyl coA oxidase messenger RNA involved in hepatic lipid peroxidation were also markedly increased in WT MCD diet-fed group. In contrast, C/EBPbeta-/- mice fed a MCD diet showed a 60% reduction in hepatic triglyceride accumulation and decreased liver injury as evidenced by reduced serum alanine aminotransferase and aspartate aminotransferase levels, and by H&E staining. Immunoblots and real-time qPCR data revealed a significant reduction in expression of stress related proteins and lipogenic genes in MCD diet-fed C/EBPbeta-/- mice. Furthermore, circulating TNFalpha and expression of acute phase response proteins CRP and SAP were significantly lower in C/EBPbeta-/- mice compared to WT mice. Conversely, C/EBPbeta over-expression in livers of WT mice increased steatosis, nuclear factor-kappaB, and endoplasmic reticulum stress, similar to MCD diet-fed mice.

Conclusion: Taken together, these data suggest a previously unappreciated molecular link between C/EBPbeta, hepatic steatosis and inflammation and suggest that increased C/EBPbeta expression may be an important factor underlying events leading to NASH.

Publication types

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

MeSH terms

  • Acute-Phase Reaction / physiopathology
  • Animals
  • Body Weight
  • CCAAT-Enhancer-Binding Protein-beta / deficiency
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-beta / physiology*
  • Choline Deficiency / complications
  • Choline Deficiency / physiopathology
  • Cytochrome P-450 CYP2E1 / biosynthesis
  • Diet
  • Disease Models, Animal
  • Endoplasmic Reticulum / physiology*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fatty Liver / etiology
  • Fatty Liver / physiopathology*
  • Inflammation / etiology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipase / metabolism
  • Liver / pathology
  • Male
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Transcription Factor CHOP / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • eIF-2 Kinase / metabolism


  • CCAAT-Enhancer-Binding Protein-beta
  • Ddit3 protein, mouse
  • Eukaryotic Initiation Factor-2
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Transcription Factor CHOP
  • Methionine
  • Cytochrome P-450 CYP2E1
  • PERK kinase
  • eIF-2 Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Lipase