Compound C attenuates NLRP3 inflammasome despite AMPK knockdown in LPS plus palmitate-induced THP-1 cells.

Abstract

NLRP3 inflammasome is a key contributor to obesity-related insulin resistance and type 2 diabetes (T2D). Adenosine monophosphate-activated protein kinase (AMPK) is a principle intracellular energy sensor exerting protective effect against T2D. Strikingly, compound C, an inhibitor of AMPK, considerably inhibited the secretion of IL-1β when THP-1 cells were stimulated with LPS plus palmitic acid (PA). The underlying mechanism was examined with respect to the effect of compound C on NLRP3 inflammasome, a multiprotein complex which controls the processing and production of IL-1β. Interestingly, compound C significantly attenuated the activation of NLRP3 inflammasome. This phenomenon was reproduced in AMPK siRNA-transfected THP-1 cells, indicating that compound C exerts this function despite AMPK knockdown. Also, it significantly suppresses the mitochondria-generated reactive oxygen species (ROS) required for NLRP3 inflammasome activation. In conclusion, compound C was shown to significantly attenuate the NLRP3 inflammasome despite AMPK knockdown, rendering it as the novel target of compound C. Potentially, compound C attenuates NLRP3 inflammasome through the suppression of mitochondrial ROS production. These findings offer initial evidence into compound C as a novel pharmacological agent with significant therapeutic potential in NLRP3 inflammasome-related disorders, including obesity, insulin resistance, and T2D. Thus, further studies are essential to identify the effect of compound C on these diseases in vitro.

• Authors: Yuxing Liu, Honghui He, Liangliang Fan, Jingjing Yuan, Hao Huang, Wenjun Yang, Linghao Wang, Zhaohui Mo, Fang Wang
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 393 Issue 1 Pg. 67-76 (01 2020) ISSN: 1432-1912 [Electronic] Germany
• PMID: 31420721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IL1B protein, human
• Inflammasomes
• Interleukin-1beta
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Palmitates
• Pyrazoles
• Pyrimidines
• Reactive Oxygen Species
• dorsomorphin
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Inflammasomes (genetics, metabolism)
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (pharmacology)
• Mitochondria (drug effects, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Palmitates (pharmacology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Reactive Oxygen Species (metabolism)
• THP-1 Cells