Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease.

Abstract

Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.

• Authors: Nami Lee, Yu Jung Heo, Sung-E Choi, Ja Young Jeon, Seung Jin Han, Dae Jung Kim, Yup Kang, Kwan Woo Lee, Hae Jin Kim
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 588 Pg. 154-160 (01 15 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 34971904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids
• Benzhydryl Compounds
• Cytokines
• Glucosides
• Inflammation Mediators
• LC15-0444
• Piperidones
• Protective Agents
• Pyrimidines
• JNK Mitogen-Activated Protein Kinases
• empagliflozin
• Choline

Topics

• Amino Acids
• Animals
• Benzhydryl Compounds (pharmacology, therapeutic use)
• Choline
• Cytokines (metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Disease Progression
• Glucosides (pharmacology, therapeutic use)
• Inflammation (pathology)
• Inflammation Mediators (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Liver (drug effects, pathology)
• Macrophage Activation (drug effects)
• Male
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Piperidones (pharmacology, therapeutic use)
• Protective Agents (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)