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Original Article

Korean J Physiol Pharmacol 2019; 23(6): 459-466

Published online November 1, 2019 https://doi.org/10.4196/kjpp.2019.23.6.459

Copyright © The Korean Journal of Physiology & Pharmacology.

Efficacy of evogliptin and cenicriviroc against nonalcoholic steatohepatitis in mice: a comparative study

Zheng Wang1, Hansu Park2, and Eun Ju Bae3,*

1College of Pharmacy, Woosuk University, Wanju 55338, 2Dong-A Socio Research Center, Dong-A ST Co., Ltd., Yongin 17073, 3College of Pharmacy, Chonbuk National University, Jeonju 54896, Korea

Correspondence to:Eun Ju Bae
E-mail: ejbae7@jbnu.ac.kr

Received: March 26, 2019; Revised: July 15, 2019; Accepted: August 26, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.

Keywords: Cenicriviroc, Dipeptidyl peptidase-4 inhibitor, Evogliptin, Fibrosis, Nonalcoholic steatohepatitis