Wang Sujuan, Gao Jiashi, Yang Meichan, Zhang Gary, Yin Lei, Tong Xin
Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Furong District, Changsha, Hunan, 410011, P. R. China.
Department of Molecular & Integrative Physiology, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA.
Adv Sci (Weinh). 2024 Dec;11(47):e2405678. doi: 10.1002/advs.202405678. Epub 2024 Oct 29.
Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.
在慢性肝损伤过程中，应激的肝细胞通过与肝星状细胞（HSCs）的通讯促进肝纤维化。然而，促进这种细胞间通讯的肝细胞内因子在很大程度上尚不明确。先前有报道称，内质网应激可强烈诱导肝细胞E4BP4，肝细胞中E4bp4的缺失可保护小鼠免受高脂饮食诱导的肝脂肪变性。在此，研究了肝细胞E4bp4缺乏如何影响肝星状细胞的激活以及向MASH相关肝纤维化的进展。在非酒精性脂肪性肝炎（NASH）饮食或四氯化碳诱导的肝纤维化小鼠模型中，肝脏E4BP4增加。肝细胞特异性E4bp4缺失可保护小鼠免受NASH饮食诱导的肝损伤、炎症和纤维化，而不影响肝脂肪变性。在培养基转移实验中，肝细胞E4BP4过表达激活了肝星状细胞，而肝细胞E4bp4缺失则产生相反的效果。RNA测序分析确定促纤维化因子骨桥蛋白（OPN）是肝细胞内E4BP4的关键靶点。抗体中和或Opn的短发夹RNA（shRNA）缺失消除了肝细胞E4BP4诱导的肝星状细胞激活。E4BP4与YAP相互作用并使其稳定，YAP是一种已确定的OPN激活剂。肝脏Yap的缺失阻止了注射Ad-E4bp4小鼠肝脏中OPN的诱导。在饮食诱导的MASH期间，肝细胞E4BP4通过YAP诱导OPN以激活肝星状细胞并促进肝纤维化。抑制肝细胞E4BP4-OPN途径可为治疗代谢相关脂肪性肝病/非酒精性脂肪性肝炎（MASLD/MASH）提供一种新的治疗途径。
