Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterised by hepatic steatosis, inflammation, and insulin resistance. The role of long noncoding RNA (lncRNA)-regulated pyroptosis in NAFLD development remains largely unknown. This study aimed to investigate whether NAFLD development is controlled by lncRNA growth-arrest specific transcript 5 (GAS5)/miR-28a-5p/membrane associated ring-CH-type finger 7 (MARCH7)-mediated pyroptosis using in vivo and in vitro models. First, GAS5 expression was decreased but miR-28a-5p expression was increased in the livers of NAFLD patients, high-fat diet (HFD)-fed mice and leptin-deficient obese (Ob/Ob) mice. Furthermore, GAS5 suppressed while miR-28a-5p promoted NAFLD development, and overexpression of miR-28a-5p reversed the GAS5 overexpression-induced attenuation of NAFLD. Mechanistically, GAS5 served as a sponge of miR-28a-5p, and miR-28a-5p enhanced pyroptosis by targeting the 3′ untranslated region (UTR) of the E3 ligase MARCH7 during NAFLD development. MARCH7 interacted with the NOD-like receptor protein 3 (NLRP3) protein, resulting in proteasomal degradation of NLRP3 to inhibit pyroptosis. As expected, MARCH7 knockdown abolished the miR-28a-5p knockdown-induced inhibition of NAFLD development, and the ubiquitin E3 ligase-inactive mutant (W589A/I556A) of MARCH7 failed to inhibit NAFLD development. In conclusion, GAS5 protected against NAFLD development by binding to miR-28a-5p, miR-28a-5p promoted NAFLD development by targeting MARCH7, and MARCH7 ameliorated NAFLD by suppressing NLRP3-mediated pyroptosis. The GAS5/miR-28a-5p/MARCH7/NLRP3 axis plays an important role in NAFLD progression, and it might be a biomarker for NAFLD.
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The original data presented in this study are included in the paper/Supplementary Material, and further inquiries can be directed to the corresponding authors.
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Acknowledgements
We thank Prof. Donghua Yang for constructive discussions.
Funding
This study was supported by the National Natural Science Foundation of China (81602636, 31600269 and 82174292), the Sichuan Science and Technology Program (2019YJ0369 and 2020YJ0401), the China Postdoctoral Science Foundation (2021M693953), the Scientific Research Project of Sichuan Medical Association (S18018), the Postdoctoral Foundation of Jiangsu (2021K385C), Disciplinary Construction Innovation Team Foundation of Chengdu Medical College (No. CMC-XK-2103), Natural Science Foundation of Sichuan Province (2022NSFSC0725) and the Collaborative Innovation Center of Sichuan for Elderly Care and Health (19Z02).
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WZ and TC conceptualised and supervised the overall project. TC, ZZ, HL, LW, AK, WG, KR, and XS performed experiments. ZZ, HL, LW, AK and YC performed validation studies. YC, WG, KR and XS performed formal data analysis. WZ, TC and ZZ drafted the paper, and all authors contributed to the methodology and revisions.
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In this study, the clinical specimen collection was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University, and all participants provided written informed consent. All animal protocols were approved by the Experimental Animal Ethics Committee of Nantong University.
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Chen, T., Meng, Y., Zhou, Z. et al. GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis. Cell Death Differ 30, 1829–1848 (2023). https://doi.org/10.1038/s41418-023-01183-4
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DOI: https://doi.org/10.1038/s41418-023-01183-4
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