PDF(Pubmed)
Abstract：
Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
摘要：
肝纤维化的特征是血管周围肝星状细胞（HSC）的激活，纤维化纳米细胞外囊泡（EV）的释放，和增加HSC糖酵解。然而，HSC的糖酵解如何通过组织区特异性途径协调纤维化扩增仍然难以捉摸。这里,我们证明，糖酵解的HSC特异性遗传抑制减少肝纤维化。此外，空间转录组学揭示了肝中心周围区的纤维化介导的EV相关途径的上调，它被糖酵解遗传抑制所废除。机械上,HSC的糖酵解通过增强启动子区组蛋白3赖氨酸9乙酰化上调EV相关基因如Ras相关蛋白Rab-31(RAB31)的表达,这增加了电动汽车的释放。功能上,这些糖酵解依赖性EV增加了受体HSC中纤维化基因的表达。此外，与糖酵解能力小鼠EV相比，源自糖酵解缺陷小鼠的EV取消了肝纤维化扩增。总之,HSC的糖酵解通过促进肝中央周围区的纤维化EV释放来放大肝纤维化，这是一个潜在的治疗靶点。
