Novel role of NLRP3-inflammasome in regulation of lipogenesis in fasting-induced hepatic steatosis

Abstract

Background:

The liver coordinates a series of metabolic adaptations to maintain the energy balance of the system and provide adequate nutrients to key organs, tissues and cells during starvation. However, the mediators and underlying molecular mechanisms that mediate these fasting-induced adaptive responses remain unclear.

Materials and methods:

Male wild-type C57BL/6J littermates (8-weeks-old) were intraperitoneally injected with MCC950 or vehicle, and then randomly divided into three groups: fed, fasted, and refed. Plasma IL1β and insulin levels were detected by ELISA kits. Plasma and hepatic metabolites were determined using commercial assay kits. HepaRG cell line was applied to verify the regulation of NLRP3 on lipogenesis.

Results:

NOD-like receptor protein 3 (NLRP3) and its downstream inflammatory cytokines were significantly suppressed after 24 h fasting and recovered upon 6 h refeeding in plasma and liver tissues of mice. Moreover, fasting-induced hepatic steatosis and accompanied liver injury were ameliorated when mice were intraperitoneally injected with MCC950 (a selective NLRP3 inhibitor). Further study revealed that MCC950 suppressed sterol regulatory element-binding protein-1c (SREBP-1c) expression and transcriptional activity, thus inhibited lipogenesis in the liver, which may explain its role in stabilizing lipid metabolism.

Conclusion:

The NLRP3 inhibitor-MCC950 protects against fasting-induced hepatic steatosis. The novel and critical role of NLRP3 in lipogenesis may explain its importance in regulating the adaptive responses of the liver upon starvation stress and may provide therapeutic value.

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Keywords:

• metabolic homeostasis
• starvation stress
• NLRP3
• MCC950
• SREBP-1c

Acknowledgments

This work was supported by National Natural Science Foundation of China (No: 81670351) and Graduates’ Innovation Fund, Huazhong University of Science and Technology (No: 5003530056 and 5003530057). Dr Baoqing Liu and Dr Xiaoxiang Mao contributed equally as co-first authors.

Disclosure

The authors report no conflicts of interest in this work.

Supplementary materials

Figure S1 β-Actin does not differ between groups. Real-time qPCR indicated that housekeeping gene 18S and β-actin do not differ between groups. n=8 per group.

Figure S2 Inhibition of NLRP3-inflammasome reduced the protein level of lipogenesis-related genes. Densitometric analysis for FASN and ACC1 in fasted and refed mice treated with MCC950 or vehicle. * P˂0.05, and ** P˂0.01 compared to the fasted group treated with vehicle, ^#P˂0.05, ^##P˂0.01 and ^###P˂0.001 compared to the vehicle group under the same diet treatment.

Figure S3 The NLRP3-inflammasome can be activated by PA treatment and inhibited by MCC950 in a concentration-dependent way in HepaRG cell line. Western blot of NLRP3 in HepaRG indicated that PA treatment activates NLRP3 inflammasome, which could be suppressed by MCC950.