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

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are oral antidiabetic agents with known liver fibrosis amelioration effects.
• The precise protective mechanisms of DPP-4Is against liver fibrosis are not fully understood.
• Gemigliptin, a DPP-4I, was investigated for its potential to mitigate liver fibrosis progression.

Purpose of the Study:

• To elucidate the effects and mechanisms of gemigliptin in liver fibrosis.
• To assess gemigliptin's impact on activated hepatic stellate cells (HSCs) and in a nonalcoholic steatohepatitis (NASH) mouse model.

Main Methods:

• Experiments were conducted on LX-2 cells (human HSCs) activated by succinate.
• In vivo studies utilized a mouse model of NASH-induced liver fibrosis.
• Assessed fibrogenesis markers, HSC proliferation, mitochondrial reactive oxygen species (ROS), and mitochondrial fission.

Main Results:

• Gemigliptin reduced fibrogenesis markers and HSC proliferation.
• It decreased succinate-induced mitochondrial ROS, intracellular ROS, and mitochondrial fission in HSCs.
• Gemigliptin alleviated liver fibrosis and mitochondrial dysfunction in the NASH mouse model.

Conclusions:

• Gemigliptin protects against HSC activation and liver fibrosis.
• This protection is mediated by alleviating mitochondrial dysfunction and ROS production.
• Gemigliptin shows potential as a therapeutic strategy for preventing liver disease development.