Korean J Physiol Pharmacol.  2019 Nov;23(6):459-466. 10.4196/kjpp.2019.23.6.459.

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

• Wang Z
• Park H
• Bae EJ

• KMID: 2461038
• DOI: http://doi.org/10.4196/kjpp.2019.23.6.459

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.

Keyword

Cenicriviroc; Dipeptidyl peptidase-4 inhibitor; Evogliptin; Fibrosis; Nonalcoholic steatohepatitis

MeSH Terms

Animals
Diet
Dipeptidyl-Peptidase IV Inhibitors
Fatty Liver
Fibrosis
Humans
Hypoglycemic Agents
Inflammation
Insulin
Insulin Resistance
Mice*
Non-alcoholic Fatty Liver Disease*
Plasma
Triglycerides
Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents
Insulin

Figure

• 

  Fig. 1 Glucose tolerance test (GTT) and insulin tolerance test (ITT) in mice fed a normal chow diet (NCD) or high-fat and high-fructose diet (HFHF) with or without evogliptin (EVO) or cenicriviroc (CVC). (A) GTT (1 g/kg glucose i.p.) and (B) ITT (0.75 U/kg insulin i.p.) were performed at 8 weeks after drug administration in mice. Area under the curve (AUC) were shown. (C) Plasma levels of insulin were analyzed by ELISA. Values are mean ± SD; n = 9–12 per group. ***p < 0.001 vs. NCD; #p < 0.05 and ##p < 0.01 vs. HFHF.

• 

  Fig. 2 Liver histology and gene expression analysis for fibrosis and inflammatory genes. (A) Triglyceride (TG) concentrations in liver and plasma were measured with a specific TG assay kit (n = 10). (B) Representative microphotographs of liver sections stained with hematoxylin eosin (H&E), Sirius red or antibodies against F4/80 or CD11b. The number of F4/80-positive cells were counted and expressed as a percentage of total hepatocytes (n = 4). The Sirius red–positive area was determined with Image J (n = 4). Original magnification ×200. Scale bars = 250 µm. (C) Plasma levels of TNFα were measured using specific ELISA kits (n = 10). (D) mRNA expression for inflammatory genes, cytokines and chemokines was determined by qPCR (n = 9–12 per group). (E) Expression level of α-smooth muscle actin (α-SMA) protein was determined by western blot in liver tissues. Representative blot and quantification results are shown (n = 9–12 per group). NCD, normal chow diet; HFHF, high-fat and high-fructose diet; EVO, evogliptin; CVC, cenicriviroc. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. NCD; #p < 0.05, ##p < 0.01 and ###p < 0.001 vs. HFHF.

• 

  Fig. 3 Nonalcoholic fatty liver disease (NAFLD) activity scores (NAS) was determined by the degree of steatosis, lobular inflammation and hepatocyte ballooning after 8 week feeding of evogliptin (EVO) or cenicriviroc (CVC) in 20 week high-fat and high-fructose diet (HFHF) study. Data are mean ± SD (n = 9 per group). **p < 0.01 vs. NCD; ##p < 0.01 vs. HFHF.

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