Sun Chuanzheng, Gao Min, Hu Haotian, Qi Jing, Tang Yishu, Cao Xiaoxue, Zhang Runbang, Liu Huaizheng
Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, P.R. China.
Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, P.R. China.
iScience. 2024 May 3;27(6):109870. doi: 10.1016/j.isci.2024.109870. eCollection 2024 Jun 21.
Autophagy enhancement in septic liver injury can play a protective role. Nerveless, the mechanism of autophagy-mediated septic liver injury needs further investigation. Our study demonstrated that in septic condition, GLI Family Zinc Finger 2 (GLI2) was elevated, whereas peroxisome-proliferator-activated receptor α (PPARα) was downregulated. Suppressing GLI2 or synovialapoptosis inhibitor 1 (SYVN1) in LPS-exposed cells increased PPARα levels, enhanced cell viability and autophagy, while inhibiting apoptosis. LPS enhanced the GLI2-SYVN1 promoter binding. SYVN1 fostered ubiquitin-mediated degradation of PPARα. IGF2BP3 stabilized GLI2 mRNA by targeting its mA site. Silencing IGF2BP3 led to decreased GLI2 and SYVN1 but increased PPARα levels, promoting cell survival and autophagy, while repressing apoptosis. This was counteracted by SYVN1 overexpression. In cecal ligation and puncture mice, IGF2BP3, SYVN1, or GLI2 knockdown ameliorated liver damage and augmented autophagy. In summary, IGF2BP3 enhanced GLI2 stability, overexpressed GLI2 subsequent promoted SYVN1 levels by interacting with its promoter, leading to ubiquitinated degradation of PPARα, thereby inhibiting PPARα-mediated autophagy and then exacerbating liver injury in sepsis.
脓毒症肝损伤中自噬增强可发挥保护作用。然而，自噬介导脓毒症肝损伤的机制仍需进一步研究。我们的研究表明，在脓毒症状态下，GLI家族锌指蛋白2（GLI2）升高，而过氧化物酶体增殖物激活受体α（PPARα）下调。在暴露于脂多糖（LPS）的细胞中抑制GLI2或滑膜凋亡抑制因子1（SYVN1）可提高PPARα水平，增强细胞活力和自噬，同时抑制细胞凋亡。LPS增强了GLI2与SYVN1启动子的结合。SYVN1促进PPARα的泛素介导降解。胰岛素样生长因子2结合蛋白3（IGF2BP3）通过靶向GLI2的mA位点来稳定其mRNA。沉默IGF2BP3导致GLI2和SYVN1水平降低，但PPARα水平升高，促进细胞存活和自噬，同时抑制细胞凋亡。而SYVN1过表达可抵消这一作用。在盲肠结扎和穿刺小鼠中，敲低IGF2BP3、SYVN1或GLI2可改善肝损伤并增强自噬。综上所述，IGF2BP3增强了GLI2的稳定性，随后GLI2过表达通过与SYVN1启动子相互作用促进SYVN1水平升高，导致PPARα的泛素化降解，从而抑制PPARα介导的自噬，进而加重脓毒症时的肝损伤。
