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RNA adenosine deaminase (ADAR1) alleviates high-fat diet-induced nonalcoholic fatty liver disease by inhibiting NLRP3 inflammasome

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease in which nucleotide-binding domain of leucine-rich repeat protein 3 (NLRP3) inflammasome plays an important role. The present research was aimed to explore the protective function of ADAR1, an RNA editing enzyme, against inflammatory damages in high-fat diet (HFD)-induced NAFLD through inhibiting NLRP3 inflammasome and subsequent inflammation. A total of 30 patients with NAFLD were investigated, and ADAR1 mRNA expression in peripheral blood monocytes surveyed. The in vivo study used lentivirus to explore the function of ADAR1 overexpression in the HFD-induced mouse model of NAFLD. The in vitro study used lentivirus and siRNA to explore the function of ADAR1 on the NLRP3 inflammasome activation in THP-1 cells. Results shown that the ADAR1 expression was upregulated in NAFLD patients in comparison to healthy controls. In vivo, the upregulation of ADAR1 impaired NLRP3 inflammasome activation and alleviated liver disease in HFD mice in comparison to the control group. Moreover, ADAR1 overexpression attenuated NLRP3 inflammasome in lipopolysaccharide (LPS)+ palmitic acid (PA)-induced THP-1 cells, while ADAR1 knockdown increased the NLRP3 inflammasome activation. Furthermore, we speculated that c-Jun may participate in ADAR1’s inhibition of NLRP3 inflammasome. Our results suggested that ADAR1 is a potential treatment target for NAFLD via regulating the activation of NLRP3 inflammasome.

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Fig. 1: ADAR1 gene expression was upregulated in NAFLD patients.
Fig. 2: ADAR1 is upregulated in HFD mice.
Fig. 3: ADAR1 protects mice from HFD-induced obesity and alleviates HFD-induced hepatic steatosis.
Fig. 4: ADAR1 ameliorates HFD-induced lipid accumulation and inflammatory response in liver.
Fig. 5: ADAR1 suppresses NLRP3 inflammasome activation in LPS + PA-induced THP-1 cells.
Fig. 6: c-Jun may participate in ADAR1’s regulation of NLRP3 inflammasome.
Fig. 7: C-Jun knockdown could abolish the effect of ADAR1 knockdown on NLRP3 expression.

Data availability

The sample set of GSE72756 was acquired from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). All the data and materials supporting the conclusion of the present study have been included within the article.

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Funding

This study was funded by the National Natural Science Foundation of China (81970403, 81400831, 82000427), National Natural Science Foundation of Hunan province (2020JJ5785, 2021JJ40948), Changsha Municipal Natural Science Foundation (kq2014256), Scientific research project of Hunan Provincial Health Commission (202203065271), the Fundamental Research Funds for the Central Universities of Central South University (2021zzts0079) and Hunan Provincial Innovation Foundation for Postgraduate (CX20210177).

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FW and RX conceived and designed this study. YXL conducted experiments. LLF contributed new reagents or analytical tools. BYJ analyzed the data. FW and YXL wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Fang Wang.

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This study was approved by the Ethics Committee of the Third Xiangya Hospital of the Central South University. Written informed consent was obtained from all study participants. All animal protocols were approved by the Institutional Animal Care and Use Committee of Central South University.

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Xiang, R., Liu, Y., Fan, L. et al. RNA adenosine deaminase (ADAR1) alleviates high-fat diet-induced nonalcoholic fatty liver disease by inhibiting NLRP3 inflammasome. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00805-8

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