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C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis.
Lab Invest. 2016 08; 96(8):895-908.LI

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+Show Affiliations

Division of Digestive Diseases, Emory University, Atlanta, GA. Atlanta VA Medical Center, Decatur, GA.Atlanta VA Medical Center, Decatur, GA.Division of Digestive Diseases, Emory University, Atlanta, GA.Division of Digestive Diseases, Emory University, Atlanta, GA. Atlanta VA Medical Center, Decatur, GA.Division of Digestive Diseases, Emory University, Atlanta, GA.Department of Pathology, Emory University Hospital, Atlanta, GA.Division of Digestive Diseases, Emory University, Atlanta, GA. Atlanta VA Medical Center, Decatur, GA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27239734

Citation

Rahman, Khalidur, et al. "C/EBP Homologous Protein Modulates Liraglutide-mediated Attenuation of Non-alcoholic Steatohepatitis." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 96, no. 8, 2016, pp. 895-908.
Rahman K, Liu Y, Kumar P, et al. C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis. Lab Invest. 2016;96(8):895-908.
Rahman, K., Liu, Y., Kumar, P., Smith, T., Thorn, N. E., Farris, A. B., & Anania, F. A. (2016). C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis. Laboratory Investigation; a Journal of Technical Methods and Pathology, 96(8), 895-908. https://doi.org/10.1038/labinvest.2016.61
Rahman K, et al. C/EBP Homologous Protein Modulates Liraglutide-mediated Attenuation of Non-alcoholic Steatohepatitis. Lab Invest. 2016;96(8):895-908. PubMed PMID: 27239734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis. AU - Rahman,Khalidur, AU - Liu,Yunshan, AU - Kumar,Pradeep, AU - Smith,Tekla, AU - Thorn,Natalie E, AU - Farris,Alton B, AU - Anania,Frank A, Y1 - 2016/05/30/ PY - 2015/11/09/received PY - 2016/04/15/revised PY - 2016/04/26/accepted PY - 2016/5/31/entrez PY - 2016/5/31/pubmed PY - 2017/6/20/medline SP - 895 EP - 908 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab. Invest. VL - 96 IS - 8 N2 - 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. SN - 1530-0307 UR - https://www.unboundmedicine.com/medline/citation/27239734/C/EBP_homologous_protein_modulates_liraglutide_mediated_attenuation_of_non_alcoholic_steatohepatitis_ L2 - http://dx.doi.org/10.1038/labinvest.2016.61 DB - PRIME DP - Unbound Medicine ER -