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.
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The study was funded by the New Xiangya Talent Project of the Third Xiangya Hospital of Central South University (No. JY201718).
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FW and ZHM conceived and designed the research. YXL conducted the main experiments. HHH and JJY contributed the new reagents and analytical tools. LLF and HH conducted the supplementary experiments during the revision. YXL, HHH, WJY, and LHW analyzed the data. FW wrote the manuscript. All authors read and approved the manuscript.
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Liu, Y., He, H., Fan, L. et al. Compound C attenuates NLRP3 inflammasome despite AMPK knockdown in LPS plus palmitate-induced THP-1 cells. Naunyn-Schmiedeberg's Arch Pharmacol 393, 67–76 (2020). https://doi.org/10.1007/s00210-019-01712-4
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DOI: https://doi.org/10.1007/s00210-019-01712-4