Skip Navigation
Skip to contents

Diabetes Metab J : Diabetes & Metabolism Journal

Search
OPEN ACCESS

Search

Page Path
HOME > Search
2 "Inflammasomes"
Filter
Filter
Article category
Keywords
Publication year
Authors
Funded articles
Original Articles
Obesity and Metabolic Syndrome
PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages
Seung Il Jo, Jung Hwan Bae, Seong Jin Kim, Jong Min Lee, Ji Hun Jeong, Jong-Seok Moon
Diabetes Metab J. 2019;43(5):683-699.   Published online October 24, 2019
DOI: https://doi.org/10.4093/dmj.2019.0112
  • 5,777 View
  • 67 Download
  • 4 Web of Science
  • 2 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Chronic inflammation has been linked to insulin resistance and type 2 diabetes mellitus (T2DM). High-fat diet (HFD)-derived fatty acid is associated with the activation of chronic inflammation in T2DM. PF-04620110, which is currently in phase 1 clinical trials as a selective acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) inhibitor, is a potent anti-diabetic agent that may be important for the regulation of chronic inflammation in T2DM. However, the mechanisms by which PF-04620110 regulates fatty acid-induced chronic inflammation remain unclear.

Methods

PF-04620110 was used in vitro and in vivo. DGAT1-targeting gRNAs were used for deletion of mouse DGAT1 via CRISPR ribonucleoprotein (RNP) system. The activation of NLRP3 inflammasome was measured by immunoblot or cytokine analysis in vitro and in vivo.

Results

Here we show that PF-04620110 suppressed fatty acid-induced nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome activation in macrophages. In contrast, PF-04620110 did not change the activation of the NLR family, CARD-domain-containing 4 (NLRC4), or the absent in melanoma 2 (AIM2) inflammasomes. Moreover, PF-04620110 inhibited K+ efflux and the NLRP3 inflammasome complex formation, which are required for NLRP3 inflammasome activation. PF-04620110 reduced the production of interleukin 1β (IL-1β) and IL-18 and blood glucose levels in the plasma of mice fed HFD. Furthermore, genetic inhibition of DGAT1 suppressed fatty acid-induced NLRP3 inflammasome activation.

Conclusion

Our results suggest that PF-04620110 suppresses fatty acid-induced NLRP3 inflammasome activation.

Citations

Citations to this article as recorded by  
  • Drug Targeting of Acyltransferases in the Triacylglyceride and 1-O-AcylCeramide Biosynthetic Pathways
    Maria Hernandez-Corbacho, Daniel Canals
    Molecular Pharmacology.2024; 105(3): 166.     CrossRef
  • Possible therapeutic targets for NLRP3 inflammasome-induced breast cancer
    Xixi Wang, Junyi Lin, Zhe Wang, Zhi Li, Minghua Wang
    Discover Oncology.2023;[Epub]     CrossRef
Complications
Gemigliptin Attenuates Renal Fibrosis Through Down-Regulation of the NLRP3 Inflammasome
Jung Beom Seo, Yeon-Kyung Choi, Hye-In Woo, Yun-A Jung, Sungwoo Lee, Seunghyeong Lee, Mihyang Park, In-Kyu Lee, Gwon-Soo Jung, Keun-Gyu Park
Diabetes Metab J. 2019;43(6):830-839.   Published online March 5, 2019
DOI: https://doi.org/10.4093/dmj.2018.0181
  • 5,749 View
  • 132 Download
  • 24 Web of Science
  • 24 Crossref
AbstractAbstract PDFPubReader   
Background

The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.

Methods

We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.

Results

Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with the in vivo results, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.

Conclusion

The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.

Citations

Citations to this article as recorded by  
  • Novel pharmacological interventions for diabetic kidney disease
    Seng Kiong Tan, Jairo A. Pinzon-Cortes, Mark E. Cooper
    Current Opinion in Nephrology & Hypertension.2024; 33(1): 13.     CrossRef
  • Integrated analysis reveals crosstalk between pyroptosis and immune regulation in renal fibrosis
    Fengxia Bai, Longchao Han, Jifeng Yang, Yuxiu Liu, Xiangmeng Li, Yaqin Wang, Ruijian Jiang, Zhaomu Zeng, Yan Gao, Haisong Zhang
    Frontiers in Immunology.2024;[Epub]     CrossRef
  • Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney
    Shanshan Li, Xuedie Gu, Muyue Zhang, Qihang Jiang, Tong Xu
    Science of The Total Environment.2024; 926: 171817.     CrossRef
  • Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation
    Linfeng Zheng, Wenjuan Mei, Jing Zhou, Xin Wei, Zhijuan Huang, Xiaozhen Lin, Li Zhang, Wei Liu, Qian Wu, Jinhong Li, Yan Yan
    Experimental and Therapeutic Medicine.2024;[Epub]     CrossRef
  • HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome
    Jialin Li, Qisheng Lin, Xinghua Shao, Shu Li, Xuying Zhu, Jingkui Wu, Shan Mou, Leyi Gu, Qin Wang, Minfang Zhang, Kaiqi Zhang, Jiayue Lu, Zhaohui Ni
    Cell Death & Disease.2023;[Epub]     CrossRef
  • Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance
    Ya Liu, Haibo Lei, Wenyou Zhang, Qichang Xing, Renzhu Liu, Shiwei Wu, Zheng Liu, Qingzi Yan, Wencan Li, Xiang Liu, Yixiang Hu
    Cell Death & Disease.2023;[Epub]     CrossRef
  • Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives
    Yu Wang, Mingyue Jin, Chak Kwong Cheng, Qiang Li
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
  • Hederagenin inhibits high glucose‐induced fibrosis in human renal cells by suppression of NLRP3 inflammasome activation through reducing cathepsin B expression
    Guohua Yang, Wang Yang, Hairong Jiang, Qing Yi, Wei Ma
    Chemical Biology & Drug Design.2023; 102(6): 1409.     CrossRef
  • Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis
    Rikke Nørregaard, Henricus A. M. Mutsaers, Jørgen Frøkiær, Tae-Hwan Kwon
    Physiological Reviews.2023; 103(4): 2847.     CrossRef
  • Adenine model of chronic renal failure in rats to determine whether MCC950, an NLRP3 inflammasome inhibitor, is a renopreventive
    Mahmoud S. Sabra, Fahmy K. Hemida, Essmat A. H. Allam
    BMC Nephrology.2023;[Epub]     CrossRef
  • Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome
    Yun Zhang, Song Zhang, Bolin Li, Yingchun Luo, Yongtai Gong, Xuexin Jin, Jiawei Zhang, Yun Zhou, Xiaozhen Zhuo, Zixi Wang, Xinbo Zhao, Xuejie Han, Yunlong Gao, Hui Yu, Desen Liang, Shiqi Zhao, Danghui Sun, Dingyu Wang, Wei Xu, Guangjin Qu, Wanlan Bo, Dan
    Cardiovascular Research.2022; 118(3): 785.     CrossRef
  • The NLRP3 inflammasome in fibrosis and aging: The known unknowns
    Yanqing Liu, Xuezeng Xu, Wangrui Lei, Yuxuan Hou, Yan Zhang, Ran Tang, Zhi Yang, Ye Tian, Yanli Zhu, Changyu Wang, Chao Deng, Shaofei Zhang, Yang Yang
    Ageing Research Reviews.2022; 79: 101638.     CrossRef
  • Research progress of endothelial‐mesenchymal transition in diabetic kidney disease
    Ying Chen, Hang Zou, Hongwei Lu, Hong Xiang, Shuhua Chen
    Journal of Cellular and Molecular Medicine.2022; 26(12): 3313.     CrossRef
  • Exploring the mechanism of Shendi Bushen capsule in anti-renal fibrosis using metabolomics theory and network analysis
    Tianwei Meng, Hong Chang, Hongyu Meng
    Molecular Omics.2022; 18(9): 873.     CrossRef
  • Gemigliptin suppresses salivary dysfunction in streptozotocin-induced diabetic rats
    Wan Seok Kang, Woo Kwon Jung, Su-Bin Park, Hyung Rae Kim, Junghyun Kim
    Biomedicine & Pharmacotherapy.2021; 137: 111297.     CrossRef
  • Long‐Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension and Renal and Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats
    Edwin K. Jackson, Zaichuan Mi, Delbert G. Gillespie, Dongmei Cheng, Stevan P. Tofovic
    Journal of the American Heart Association.2021;[Epub]     CrossRef
  • Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis
    Yu Zhang, Ruicheng Zhang, Xiaohu Han
    Inflammation Research.2021; 70(5): 543.     CrossRef
  • Inflammasome as an Effective Platform for Fibrosis Therapy
    Ting-Ting Chen, Feng Xiao, Nan Li, Shan Shan, Meng Qi, Zi-Ying Wang, Sheng-Nan Zhang, Wei Wei, Wu-Yi Sun
    Journal of Inflammation Research.2021; Volume 14: 1575.     CrossRef
  • Targeting Dermal Fibroblast Subtypes in Antifibrotic Therapy: Surface Marker as a Cellular Identity or a Functional Entity?
    Xin Huang, Yimin Khoong, Chengyao Han, Dai Su, Hao Ma, Shuchen Gu, Qingfeng Li, Tao Zan
    Frontiers in Physiology.2021;[Epub]     CrossRef
  • Linagliptin Protects against Endotoxin-Induced Acute Kidney Injury in Rats by Decreasing Inflammatory Cytokines and Reactive Oxygen Species
    Tsung-Jui Wu, Yi-Jen Hsieh, Chia-Wen Lu, Chung-Jen Lee, Bang-Gee Hsu
    International Journal of Molecular Sciences.2021; 22(20): 11190.     CrossRef
  • Psidium guajava Flavonoids Prevent NLRP3 Inflammasome Activation and Alleviate the Pancreatic Fibrosis in a Chronic Pancreatitis Mouse Model
    Guixian Zhang, Liming Tang, Hongbin Liu, Dawei Liu, Manxue Wang, Jun Cai, Weijun Liu, Wei Nie, Yi Zhang, Xiaomeng Yu
    The American Journal of Chinese Medicine.2021; 49(08): 2001.     CrossRef
  • Effect and Regulation of the NLRP3 Inflammasome During Renal Fibrosis
    Hong Zhang, Zhengchao Wang
    Frontiers in Cell and Developmental Biology.2020;[Epub]     CrossRef
  • Zhen-Wu-Tang Protects IgA Nephropathy in Rats by Regulating Exosomes to Inhibit NF-κB/NLRP3 Pathway
    Honglian Li, Ruirui Lu, Yu Pang, Jicheng Li, Yiwen Cao, Hongxin Fu, Guoxing Fang, Qiuhe Chen, Bihao Liu, Junbiao Wu, Yuan Zhou, Jiuyao Zhou
    Frontiers in Pharmacology.2020;[Epub]     CrossRef
  • Protective effect of exogenous hydrogen sulfide on diaphragm muscle fibrosis in streptozotocin-induced diabetic rats
    Rui Yang, Qiang Jia, Yan Li, Shomaila Mehmood
    Experimental Biology and Medicine.2020; 245(14): 1280.     CrossRef

Diabetes Metab J : Diabetes & Metabolism Journal
Close layer