脂毒性
脂肪性肝炎
甾醇调节元件结合蛋白
脂肪肝
内科学
内分泌学
胰岛素抵抗
下调和上调
生物
脂质体
背景(考古学)
脂质代谢
胆固醇
细胞生物学
胰岛素
医学
生物化学
甾醇
疾病
基因
古生物学
作者
Vian Azzu,Michèle Vacca,Ioannis Kamzolas,Zoe Hall,Jack Leslie,Stefania Carobbio,Samuel Virtue,Susan Davies,Agnes Lukasik,Martin Dale,Mohammad Bohlooly‐Y,Animesh Acharjee,Daniel Lindén,Guillaume Bidault,Evangelia Petsalaki,Julian L. Griffin,Fiona Oakley,Michael Allison,Antonio Vidal–Puig
标识
DOI:10.1016/j.molmet.2021.101210
摘要
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.
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