Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression.
Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression.
复制标题
胰岛素诱导基因1（INSIG1）功能的抑制促进肝脏脂质重塑并抑制非酒精性脂肪性肝炎（NASH）的进展。
DOI：
10.1016/j.molmet.2021.101210
复制
发表时间：
2021-06
影响因子：
8.1
通讯作者：
Vidal-Puig A
中科院分区：
文献类型：
--
作者：
Azzu V;Vacca M;Kamzolas I;Hall Z;Leslie J;Carobbio S;Virtue S;Davies SE;Lukasik A;Dale M;Bohlooly-Y M;Acharjee A;Lindén D;Bidault G;Petsalaki E;Griffin JL;Oakley F;Allison MED;Vidal-Puig A
非酒精性脂肪性肝病（NAFLD）是一种与肥胖和代谢综合征相关的无声流行病，也会增加心血管和糖尿病相关的发病率和死亡率。缺乏对调节非酒精性脂肪性肝炎（NASH）进展的适应性代偿代谢程序的完整理解。NASH患者肝活检的转录组学分析显示，NASH进展与代谢途径的重新连接有关，包括从头脂质/胆固醇合成和脂肪酸重塑的上调。这些代谢程序的调节是通过激活固醇调节元件结合蛋白（SREBP）转录网络来实现的;然而，在NASH的背景下，SREBP的激活是否作为脂毒性的致病驱动因素，或者更确切地说，促进保护性脂质的生物合成，缓冲过度的脂质积累，预防炎症和纤维化，仍然存在争议。为了阐明SCAP/SREBP在NASH和伤口愈合反应中的病理生理学作用，我们使用了用NASH诱导饮食攻击的Insig 1缺陷（具有超高效SREBP）小鼠模型。尽管脂质和胆固醇生物合成增强，Insig 1 KO小鼠与Het/WT同窝出生小鼠具有相似的全身代谢和胰岛素敏感性。此外，激活SREBP导致脂质体重构，减少肝细胞损伤，并改善伤口愈合反应。我们的研究提供了关于NAFLD发病机制的途径和机制的可操作知识，这可能对开发新的治疗策略有用。我们的研究结果还表明，SCAP/SREBP/INSIG 1三重奏管理旨在保护肝脏免受NASH脂毒性损伤的转录程序。人类NASH活检的转录组学分析以代谢途径重新布线为特征。SCAP/SREBP/INSIG 1调节促进NASH中的脂质/胆固醇合成/重塑。Insig 1的缺失促进脂质重塑，防止NASH中的肝脏脂毒性。Insig 1的缺失改善了肝损伤和伤口愈合，并抑制了NASH的进展。
Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH. Human NASH biopsies’ transcriptomics analysis features metabolic pathway rewiring. SCAP/SREBP/INSIG1 modulation promotes lipid/cholesterol synthesis/remodelling in NASH. Loss of Insig1 promotes lipid remodelling, preventing hepatic lipotoxicity in NASH. Loss of Insig1 improves liver damage and wound healing and restrains NASH progression.
登录
查看更多内容
Insig1/SREBP1/SCD1 设定点的适应性变化有助于脂肪组织应对因肥胖而增加的储存需求。
影响因子：
7.7
作者：
Carobbio S;Hagen RM;Lelliott CJ;Slawik M;Medina-Gomez G;Tan CY;Sicard A;Atherton HJ;Barbarroja N;Bjursell M;Bohlooly-Y M;Virtue S;Tuthill A;Lefai E;Laville M;Wu T;Considine RV;Vidal H;Langin D;Oresic M;Tinahones FJ;Fernandez-Real JM;Griffin JL;Sethi JK;López M;Vidal-Puig A
通讯作者：
Vidal-Puig A
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
7.3
作者：
Howie D;Ten Bokum A;Necula AS;Cobbold SP;Waldmann H
通讯作者：
Waldmann H
影响因子：
13.5
作者：
Hall, Zoe;Chiarugi, Davide;Griffin, Julian L.
通讯作者：
Griffin, Julian L.
影响因子：
29.4
作者：
Azzu, Vian;Vacca, Michele;Vidal-Puig, Antonio
通讯作者：
Vidal-Puig, Antonio