Dipeptidyl peptidase-4 inhibitors (DPP-4i) are useful antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP-4). As DPP-4 targets diverse substrates besides incretin, DPP-4i may exert nonglycemic pleiotropic effects. Recent studies have reported that hepatic DPP-4 expression is upregulated under nonalcoholic steatohepatitis (NASH) condition in animals and humans. We investigated whether DPP-4i could ameliorate the pathological phenotype of NASH and evaluated the underlying mechanisms in a mouse model. Mice were randomly assigned to one of three groups: Group 1, chow-fed mice with vehicle treatment for 20 weeks; group 2, high-fat, high-fructose, and high-cholesterol AMLN diet-fed mice with vehicle treatment for 20 weeks; group 3, AMLN diet-fed mice with vehicle treatment for 10 weeks followed by DPP-4i (teneligliptin 20 mg/kg/day by oral gavage) treatment for 10 weeks. Serum and liver tissues were analyzed. Administration of DPP-4i significantly reduced the body weight, liver to body weight ratio, and serum liver enzyme levels in AMLN diet-induced NASH model. DPP-4i-treated AMMN diet-fed mice revealed a marked alleviation in liver steatosis and fibrosis compared with vehicle-treated AMLN-fed mice. NASH alleviation in vivo significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and decreased DPP-4 expression in the liver. In vitro assay of palmitate-treated hepatocytes, treatment with DPP-4i significantly attenuated the hallmarks of TRAIL receptor-mediated lipoapoptosis, suppressing DPP-4 expression. DPP-4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly through the modulation of hepatic DPP-4 expression.
S. Lee: None. M. Lee: None. E. Shin: None. Y. Kim: None. E. Kang: None. B. Cha: None.
Handok Inc. (2017-31-0006)