title: C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis.
abstract: The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a major transcriptional regulator of endoplasmic reticulum (ER) stress-mediated apoptosis, is implicated in lipotoxicity-induced ER stress and hepatocyte apoptosis in non-alcoholic fatty liver disease (NAFLD). We have previously demonstrated that the glucagon-like peptide-1 (GLP-1) agonist, liraglutide, protects steatotic hepatocytes from lipotoxicity-induced apoptosis by improved handling of free fatty acid (FFA)-induced ER stress. In the present study, we investigated whether CHOP is critical for GLP-1-mediated restoration of ER homeostasis and mitigation of hepatocyte apoptosis in a murine model of NASH (non-alcoholic steatohepatitis). Our data show that despite similar caloric intake, CHOP KO (CHOP(-/-)) mice fed a diet high in fat, fructose, and cholesterol (HFCD) for 16 weeks developed more severe histological features of NASH compared with wild-type (WT) controls. Severity of NASH in HFCD-fed CHOP(-/-) mice correlated with significant decrease in peroxisomal β-oxidation, and increased de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. Four weeks of liraglutide treatment markedly attenuated steatohepatitis in HFCD-fed WT mice by improving insulin sensitivity, and suppressing de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. However, in the absence of CHOP, liraglutide did not improve insulin sensitivity, nor suppress peroxisomal β-oxidation or ER stress-mediated hepatocyte apoptosis. Taken together, these data indicate that CHOP protects hepatocytes from HFCD-induced ER stress, and has a significant role in the mechanism of liraglutide-mediated protection against NASH pathogenesis.
authors.affiliation: Division of Digestive Diseases, Emory University, Atlanta, GA.|Atlanta VA Medical Center, Decatur, GA.
authors.forename: Khalidur
authors.initials: K
authors.lastname: Rahman
authors.affiliation: Atlanta VA Medical Center, Decatur, GA.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Digestive Diseases, Emory University, Atlanta, GA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Division of Digestive Diseases, Emory University, Atlanta, GA.|Atlanta VA Medical Center, Decatur, GA.
authors.forename: Tekla
authors.initials: T
authors.lastname: Smith
authors.affiliation: Division of Digestive Diseases, Emory University, Atlanta, GA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Thorn
authors.affiliation: Department of Pathology, Emory University Hospital, Atlanta, GA.
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Division of Digestive Diseases, Emory University, Atlanta, GA.|Atlanta VA Medical Center, Decatur, GA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000077270:Exenatide; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D000069450:Liraglutide / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C497249:DDIT3 protein, human; D004040:Dietary Carbohydrates; D010455:Peptides; D020011:Protective Agents; D014688:Venoms; D051742:Transcription Factor CHOP; D000069450:Liraglutide; D002784:Cholesterol; D000077270:Exenatide