GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis

作者全名："Chen, Tianxing; Meng, Yao; Zhou, Zhihang; Li, Haitao; Wan, Lingfeng; Kang, Aiwen; Guo, Wei; Ren, Ke; Song, Xueru; Chen, Yu; Zhao, Wei"

作者地址："[Chen, Tianxing; Li, Haitao; Kang, Aiwen] Nantong Univ, Inst Reprod Med, Med Sch, Nantong, Peoples R China; [Meng, Yao; Guo, Wei; Ren, Ke; Zhao, Wei] Chengdu Med Coll, Sch Lab Med, Chengdu, Peoples R China; [Zhou, Zhihang] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China; [Wan, Lingfeng] Nanjing Univ Chinese Med, Affiliated Hosp, Dept Infect Dis, Nanjing, Peoples R China; [Song, Xueru] Zhejiang Univ, Affiliated Hosp 1, Dept Pathol, Hangzhou, Zhejiang, Peoples R China; [Chen, Yu] City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China; [Chen, Yu] City Univ Hong Kong, Tung Biomed Sci Ctr, Hong Kong, Peoples R China; [Zhao, Wei] Clin Med Coll, Clin Lab, Chengdu, Peoples R China; [Zhao, Wei] Chengdu Med Coll, Affiliated Hosp 1, Chengdu, Peoples R China"

通信作者："Zhao, W (通讯作者)，Chengdu Med Coll, Sch Lab Med, Chengdu, Peoples R China.; Zhao, W (通讯作者)，Clin Med Coll, Clin Lab, Chengdu, Peoples R China.; Zhao, W (通讯作者)，Chengdu Med Coll, Affiliated Hosp 1, Chengdu, Peoples R China."

来源：CELL DEATH AND DIFFERENTIATION

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001008552800001

JCR分区：Q1

影响因子：13.7

年份：2023

卷号：30

期号：7

开始页：1829

结束页：1848

文献类型：Article

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摘要："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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