Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression

Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated th...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2020-11, Vol.10 (1), p.19429-19429, Article 19429
Main Authors: Lee, Minyoung, Shin, Eugene, Bae, Jaehyun, Cho, Yongin, Lee, Ji-Yeon, Lee, Yong-Ho, Lee, Byung-Wan, Kang, Eun Seok, Cha, Bong-Soo
Format: Article
Language:English
Subjects:
Amylin
Animals
Antidiabetics
Apoptosis
Apoptosis - drug effects
Body Weight - drug effects
Cholesterol
Diabetes mellitus
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl-peptidase IV
Dipeptidyl-Peptidase IV Inhibitors - therapeutic use
Fatty liver
Fibrosis
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Hypoglycemic Agents - therapeutic use
Liver - drug effects
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Molecular modelling
Non-alcoholic Fatty Liver Disease - metabolism
Non-alcoholic Fatty Liver Disease - prevention & control
Palmitic acid
Pathogenesis
Peptidase
Signal Transduction - drug effects
Steatosis
TRAIL protein
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-75288-y