Ma Fanglin, Longo Miriam, Meroni Marica, Bhattacharya Dipankar, Paolini Erika, Mughal Shama, Hussain Syed, Anand Sumit Kumar, Gupta Neha, Zhu Yiwei, Navarro-Corcuera Amaia, Li Kenneth, Prakash Satya, Cogliati Bruno, Wang Shuang, Huang Xin, Wang Xiaobo, Yurdagul Arif, Rom Oren, Wang Liheng, Fried Susan K, Dongiovanni Paola, Friedman Scott L, Cai Bishuang
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.
Cell Metab. 2025 May 6;37(5):1152-1170.e7. doi: 10.1016/j.cmet.2025.01.020. Epub 2025 Feb 26.
Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show that human fibrotic MASH livers have decreased EH-domain-binding protein 1 (EHBP1), a genome-wide association study (GWAS) locus associated with low-density lipoprotein (LDL) cholesterol, and that EHBP1 loss- and gain-of-function increase and decrease MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization. Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the tumor necrosis factor alpha (TNF-α)/peroxisome proliferator-activated receptor alpha (PPARα) pathway suppresses EHBP1 in MASH. These data not only provide mechanistic insights into the role of EHBP1 in cholesterol metabolism and MASH fibrosis but also elucidate an interplay between inflammation and EHBP1-mediated cholesterol metabolism.
过量胆固醇积累会导致代谢功能障碍相关脂肪性肝炎（MASH）中的纤维化，但MASH中肝脏胆固醇代谢如何失调尚不完全清楚。我们发现，人类纤维化MASH肝脏中与低密度脂蛋白（LDL）胆固醇相关的全基因组关联研究（GWAS）位点——EH结构域结合蛋白1（EHBP1）减少，并且EHBP1功能丧失和功能获得分别增加和减少小鼠的MASH纤维化。机制研究表明，EHBP1促进sortilin介导的PCSK9分泌，导致低密度脂蛋白受体（LDLR）降解、LDL摄取减少以及纤维化效应因子TAZ减少。在细胞水平上，EHBP1缺乏会影响retromer的细胞内定位，retromer是sortilin稳定所需的一种蛋白质复合物。我们稳定retromer的治疗方法在减轻MASH纤维化方面是有效的。此外，我们发现肿瘤坏死因子α（TNF-α）/过氧化物酶体增殖物激活受体α（PPARα）途径在MASH中抑制EHBP1。这些数据不仅提供了关于EHBP1在胆固醇代谢和MASH纤维化中作用的机制见解，还阐明了炎症与EHBP1介导的胆固醇代谢之间的相互作用。
