Gemigliptin Alleviates Succinate-Induced Hepatic Stellate Cell Activation by Ameliorating Mitochondrial Dysfunction

Abstract

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are used clinically as oral antidiabetic agents. Although DPP-4Is are known to ameliorate liver fibrosis, the protective mechanism of DPP-4Is in liver fibrosis remains obscure. In this study, gemigliptin was used to investigate the potential of DPP-4Is to alleviate the progression of liver fibrosis. Methods: To clarify the effects and mechanisms of gemigliptin, we conducted various experiments in LX-2 cells (immortalized human hepatic stellate cells [HSCs], the principal effectors of hepatic fibrogenesis), which were activated by succinate and exhibited elevated expression of α-smooth muscle actin, collagen type 1, and pro-inflammatory cytokines and increased cell proliferation. In vivo, we examined the effects and mechanisms of gemigliptin on a high-fat, high-cholesterol-induced mouse model of nonalcoholic steatohepatitis (NASH). Results: Gemigliptin decreased the expression of fibrogenesis markers and reduced the abnormal proliferation of HSCs. In addition, gemigliptin reduced the succinate-induced production of mitochondrial reactive oxygen species (ROS), intracellular ROS, and mitochondrial fission in HSCs. Furthermore, in the mouse model of NASH-induced liver fibrosis, gemigliptin alleviated both liver fibrosis and mitochondrial dysfunction. Conclusion: Gemigliptin protected against HSC activation and liver fibrosis by alleviating mitochondrial dysfunction and ROS production, indicating its potential as a strategy for preventing the development of liver disease.

Effect of glucagon-like peptide 1 on salivary gland hypofunction in diabetic db/db mice

“…DPP-4 inhibitors reduce ROS production, prevent mitochondrial dysfunction, improve endothelial function, and reduce vascular inflammation and oxidative stress in animal models of diabetes and its complications [42][43][44][45]. A DPP-4 inhibitor, gemigliptin, has been reported to improve liver disease and diabetes by alleviating mitochondrial dysfunction and reducing ROS production [46,47]. Based on previous studies and our results, DPP-4 and GLP-1 are attributed to the increase of ROS.…”

Improvement effect of gemigliptin on salivary gland dysfunction in exogenous methylglyoxal-injected rats

“…Using animal models of diabetes and its complications as models, DPP-4 inhibitors lower ROS production [ 38 , 39 ]. It has also been reported that gemigliptin can alleviate mitochondrial dysfunction and reduce the production of reactive oxygen species in liver disease and diabetes [ 40 , 41 ]. Previous studies and our findings indicate that gemigliptin's cytoprotective properties are due to its ability to reduce ROS levels by inhibiting DPP-4 activity.…”

Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy

“…One limitation of this study is that the MCD mouse model used in the current study shows suppression of VLDL release, which is one of the hallmarks of defective hepatic lipid metabolism in NAFLD [ 63 ]. However, previous studies have demonstrated that that gemigliptin ameliorated NASH in different mouse models, including those induced by high-fat, high-cholesterol- or Western diet-induced [ 64 , 65 ]. Consequently, these previous reports can complement the limitations of the animal model we used.…”