lc15-0444 and Fatty-Liver

Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used antihyperglycemic agents for type 2 diabetes mellitus. Recently, increasing attention has been focused on the pleiotropic actions of DPP-4 inhibitors. The aim of the present study was to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could ameliorate features of metabolic syndrome. Mice were fed a Western diet (WD) for 12 weeks and were subsequently divided into 2 groups: mice fed a WD diet alone or mice fed a WD diet supplemented with gemigliptin for an additional 4 weeks. Gemigliptin treatment attenuated WD-induced body mass gain, hypercholesterolemia, adipocyte hypertrophy, and macrophage infiltration into adipose tissue, which were accompanied by an increased expression of uncoupling protein 1 in subcutaneous fat. These events contributed to improved insulin sensitivity, as assessed by the homeostasis model assessment of insulin resistance and intraperitoneal insulin tolerance test. Furthermore, gemigliptin reduced WD-induced hepatic triglyceride accumulation via inhibition of de novo lipogenesis and activation of fatty acid oxidation, which was accompanied by AMP-dependent protein kinase activation. Gemigliptin ameliorated WD-induced hepatic inflammation and fibrosis through suppression of oxidative stress. These results suggest that DPP-4 inhibitors may represent promising therapeutic agents for metabolic syndrome beyond their current role as antihyperglycemic agents.

Topics: Adipocytes; Animals; Diet, Western; Fatty Liver; Fibrosis; Hypercholesterolemia; Hypertrophy; Inflammation; Insulin Resistance; Liver; Male; Metabolic Syndrome; Mice; Piperidones; Pyrimidines; Subcutaneous Fat; Uncoupling Protein 1; Weight Gain

Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered hepatokine that mediates obesity-related metabolic disturbances. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel therapeutic agents for inflammatory disorders including nonalcoholic fatty liver disease (NAFLD). However, no research has examined the connections or functions of LECT2 and the novel DPP-4 inhibitor, gemigliptin, in NAFLD pathogenesis. High-fat diet (HFD)-fed C57BL/6 mice were used to investigate the effect of gemigliptin on hepatic steatosis and LECT2 expression. In the HepG2 cell line, LECT2 and gemigliptin signaling were analyzed by Western blot. LECT2 increased mammalian target of rapamycin (mTOR) phosphorylation, sterol regulatory element-binding protein (SREBP)-1 cleavage, lipid accumulation, and insulin resistance in HepG2 cells; these events were significantly decreased by treatment with a c-Jun N-terminal kinase (JNK) inhibitor. Gemigliptin increased AMP-activated protein kinase (AMPK) phosphorylation and inhibited tumor necrosis factor (TNF) α-induced mTOR phosphorylation, SREBP-1 cleavage, lipid accumulation, and LECT2 expression in HepG2 cells; these events were attenuated by an AMPK inhibitor. Gemigliptin recovered TNFα-induced inhibition of insulin receptor substrate (IRS)-1 and Akt phosphorylation that was abolished in LECT2 knockdown cells or by AMPK inhibition. In preliminary in vivo experiments, gemigliptin induced AMPK phosphorylation and inhibited LECT2 expression in liver tissues from HFD-fed mice. Mice fed with HFD and gemigliptin showed improved hepatic steatosis and insulin resistance compared to HFD-fed mice. Gemigliptin might alleviate hepatic steatosis and insulin resistance by inhibiting LECT2 expression by AMPK-dependent and JNK-dependent mechanisms, suggesting a direct protective effect against NAFLD progression.

Topics: AMP-Activated Protein Kinases; Animals; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Fatty Liver; Hep G2 Cells; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Piperidones; Pyrimidines