High Glucose-Aggravated Hepatic Insulin Resistance: Role of the NLRP3 Inflammasome in Kupffer Cells.

Abstract

OBJECTIVE:

This study aimed to investigate whether the NLRP3 inflammasome in Kupffer cells (KCs) can be activated in response to high glucose (HG) and to evaluate its influence on hepatic insulin sensitivity.

METHODS:

Primary KCs and hepatocytes were isolated from mice, and lipid accumulation, glucose output, and insulin sensitivity of hepatocytes were investigated after culturing either alone or with KCs exposed to HG. The influence of HG-induced NLRP3 inflammasome activation in KCs on insulin sensitivity of hepatocytes was examined. Treatment with gadolinium trichloride caused KC depletion, and, subsequently, a streptozotocin-induced hyperglycemic mouse model was used to confirm the influence of KCs on hepatic insulin sensitivity.

RESULTS:

Hepatocytes cocultured with KCs showed enhanced lipid accumulation, glucose output, and impaired insulin sensitivity when exposed to HG. Enhanced NLRP3 inflammasome activation was also evident in both hepatocytes and KCs. Moreover, KCs that were pretreated with caspase-1 inhibitor, NLRP3 inhibitor, and NLRP3 small interfering RNA corrected coculture-induced aberrances in insulin action and NLRP3 inflammasome activation in hepatocytes. KC coculture also increased interleukin-1β (IL-1β)-mediated nuclear factor-κB (NF-κB) activation in hepatocytes. In hyperglycemic mice, KC depletion inhibited NLRP3 inflammasome activation and improved hepatic insulin sensitivity.

CONCLUSIONS:

NLRP3 inflammasome activation impaired insulin sensitivity through KC-derived IL-1β-mediated NF-κB activation in hepatocytes exposed to HG.

• Authors: Tao Zheng, Qibin Wang, Yongcheng Dong, Weidong Ma, Yonghong Zhang, Yan Zhao, Fang Bian, Li Chen
• Journal: Obesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 28 Issue 7 Pg. 1270-1282 (07 2020) ISSN: 1930-739X [Electronic] United States
• PMID: 32538511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Obesity Society.

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Glucose

Topics

• Animals
• Cells, Cultured
• Dose-Response Relationship, Drug
• Glucose (pharmacology)
• Inflammasomes (drug effects, metabolism, physiology)
• Insulin Resistance (genetics)
• Kupffer Cells (drug effects, immunology, metabolism)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)