Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, China.
School of Laboratory Medicine, Chengdu Medical College, Chengdu, China.
Cell Death Differ. 2023 Jul;30(7):1829-1848. doi: 10.1038/s41418-023-01183-4. Epub 2023 Jun 19.
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.
非酒精性脂肪性肝病 (NAFLD) 的特征是肝脂肪变性、炎症和胰岛素抵抗。长链非编码 RNA (lncRNA) 调控细胞焦亡在 NAFLD 发病机制中的作用在很大程度上尚不清楚。本研究旨在通过体内和体外模型研究非酒精性脂肪性肝病的发展是否受 lncRNA 生长停滞特异性转录物 5 (GAS5)/miR-28a-5p/膜相关环-CH 型手指 7 (MARCH7) 介导的细胞焦亡调控。首先，NAFLD 患者、高脂肪饮食 (HFD) 喂养小鼠和瘦素缺陷肥胖 (Ob/Ob) 小鼠肝脏中 GAS5 表达降低而 miR-28a-5p 表达升高。此外，GAS5 抑制而 miR-28a-5p 促进 NAFLD 发展，过表达 miR-28a-5p 逆转 GAS5 过表达引起的 NAFLD 衰减。机制上，GAS5 作为 miR-28a-5p 的海绵，在 NAFLD 发展过程中，miR-28a-5p 通过靶向 E3 连接酶 MARCH7 的 3'非翻译区 (UTR) 增强细胞焦亡。MARCH7 与 NOD 样受体蛋白 3 (NLRP3) 蛋白相互作用，导致 NLRP3 被蛋白酶体降解，从而抑制细胞焦亡。正如预期的那样，MARCH7 敲低消除了 miR-28a-5p 敲低对 NAFLD 发展的抑制作用，而 MARCH7 的泛素 E3 连接酶失活突变体 (W589A/I556A) 不能抑制 NAFLD 发展。总之，GAS5 通过与 miR-28a-5p 结合来防止 NAFLD 发展，miR-28a-5p 通过靶向 MARCH7 促进 NAFLD 发展，MARCH7 通过抑制 NLRP3 介导的细胞焦亡来改善 NAFLD。GAS5/miR-28a-5p/MARCH7/NLRP3 轴在 NAFLD 进展中起重要作用，可能是 NAFLD 的一个生物标志物。
