title: CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Shaikh Mizanoor
authors.initials: SM
authors.lastname: Rahman
authors.forename: Jill M
authors.initials: JM
authors.lastname: Schroeder-Gloeckler
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Janssen
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Qadri
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Maclean
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000210:Acute-Phase Reaction / Q000503:physiopathology; D000818:Animals; D001835:Body Weight; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D002796:Choline Deficiency / Q000150:complications / Q000503:physiopathology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D004032:Diet; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology*; D007249:Inflammation / Q000209:etiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D019392:Cytochrome P-450 CYP2E1; D015852:Eukaryotic Initiation Factor-2; D048031:JNK Mitogen-Activated Protein Kinases; D008049:Lipase; D008715:Methionine; D016328:NF-kappa B; D051742:Transcription Factor CHOP; D014409:Tumor Necrosis Factor-alpha; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse