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

Hwang, Hwan-Jin; Jung, Tae Woo; Kim, Baek-Hui; Hong, Ho Cheol; Seo, Ji A; Kim, Sin Gon; Kim, Nan Hee; Choi, Kyung Mook; Choi, Dong Seop; Baik, Sei Hyun; Yoo, Hye Jin

doi:10.1016/j.bcp.2015.08.098

Cited by 72Liver Disease Diagnosis and TreatmentAdipokines, Inflammation, and Metabolic DiseasesPeptidase Inhibition and Analysis

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

Hwang, Hwan-Jin, Jung, Tae Woo, Kim, Baek-Hui, Hong, Ho Cheol, Seo, Ji A, Kim, Sin Gon, Kim, Nan Hee, Choi, Kyung Mook +3 more·2015·Biochemical Pharmacology

DOI 10.1016/j.bcp.2015.08.098

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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.

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LECT2 alters insulin signaling through the JNK pathway in myocytes, and expression of LECT2 in liver is negatively regulated by AMPK.
“LECT2 alters insulin signaling through the JNK pathway in myocytes, and the expression of LECT2 in the liver is negatively regulated by the energy-depletion sensor AMPK [239,248,249].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [249]

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岩本, 侑., & Iwamoto, Y. (n.d.) · Institutional Repositories DataBase (IRDB) · doi:10.15111/00003071

Authors: Hwang, H.-J., Jung, T. W., Kim, B.-H., Hong, H. C., Seo, J. A., Kim, S. G., Kim, N. H., Choi, K. M., Choi, D. S., Baik, S. H., & Yoo, H. J.
Affiliations: Korea University (KR)
Corresponding author: Yoo, Hye Jin
ORCID: Hwang, Hwan-Jin
Jung, Tae Woo
Kim, Baek-Hui
Seo, Ji A
Kim, Sin Gon
Kim, Nan Hee
Choi, Kyung Mook
Choi, Dong Seop
Baik, Sei Hyun
Yoo, Hye Jin
Venue: Biochemical Pharmacology
Publisher: Elsevier BV
Published: 2015-11
Volume: 98
Issue: 1
Pages: 157-166
ISSN: 0006-2952 (ISSN-L)
DOI: 10.1016/j.bcp.2015.08.098
OpenAlex: W1196553794
Cited by: 72
References: 34
Citations by year: 2026: 1 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 4 · 2016: 5
FWCI: 3.93
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochemical Pharmacology (publishedVersion)
PubMed (publishedVersion)
Funders: Ministry of Education, Science and Technology (2015R1A1A1A05001173)
National Research Foundation of Korea
Topics: Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
Keywords: gemigliptin, DPP-4 inhibitors, LECT2, hepatokines, non-alcoholic fatty liver disease, hepatic steatosis, insulin resistance, AMPK, c-Jun N-terminal kinase, mTOR signaling, SREBP1, TNF-α, high-fat diet, lipid accumulation
MeSH terms: Animals, Dietary Fats, Fatty Liver, Humans, Insulin Resistance, Mice, Inbred C57BL, Piperidones, Pyrimidines, Intercellular Signaling Peptides and Proteins, MAP Kinase Kinase 4, Mice, Dipeptidyl-Peptidase IV Inhibitors, AMP-Activated Protein Kinases, Hep G2 Cells

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

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