A dipeptidyl peptidase-IV inhibitor improves hepatic steatosis and insulin resistance by AMPK-dependent and JNK-dependent inhibition of LECT2 expression.

Abstract

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.

• Authors: Hwan-Jin Hwang, Tae Woo Jung, Baek-Hui Kim, Ho Cheol Hong, Ji A Seo, Sin Gon Kim, Nan Hee Kim, Kyung Mook Choi, Dong Seop Choi, Sei Hyun Baik, Hye Jin Yoo
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 98 Issue 1 Pg. 157-66 (Nov 01 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 26297911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

• Dietary Fats
• Dipeptidyl-Peptidase IV Inhibitors
• Intercellular Signaling Peptides and Proteins
• LC15-0444
• Lect2 protein, mouse
• Piperidones
• Pyrimidines
• AMP-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Dietary Fats (administration & dosage, adverse effects)
• Dipeptidyl-Peptidase IV Inhibitors (therapeutic use)
• Fatty Liver (drug therapy)
• Hep G2 Cells
• Humans
• Insulin Resistance
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• MAP Kinase Kinase 4 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Piperidones (therapeutic use)
• Pyrimidines (therapeutic use)