PDF(Pubmed)
Abstract：
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 m6A 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.
摘要：
自噬增强在脓毒症肝损伤中可以起到保护作用。没有神经，自噬介导的脓毒症肝损伤机制有待进一步研究。我们的研究表明，在败血症条件下，GLI家族锌指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LPS的细胞中抑制GLI2或滑膜细胞凋亡抑制剂1(SYVN1)增加PPARα水平,增强细胞活力和自噬，同时抑制细胞凋亡。LPS增强GLI2-SYVN1启动子结合。SYVN1促进泛素介导的PPARα降解。IGF2BP3通过靶向其m6A位点来稳定GLI2mRNA。沉默IGF2BP3导致GLI2和SYVN1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。这被SYVN1过表达抵消。在盲肠结扎和穿刺小鼠中，IGF2BP3、SYVN1或GLI2敲低可改善肝脏损伤并增强自噬。总之,IGF2BP3增强GLI2稳定性，过表达GLI2随后通过与其启动子相互作用促进SYVN1水平，导致PPARα的泛素化降解，从而抑制PPARα介导的自噬，然后加剧脓毒症的肝损伤。
