Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl₄, and (iv) a combination of CCl₄ injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.

酰基辅酶 A 结合蛋白 （ACBP），也称为地西泮结合抑制剂 （DBI），是自噬的细胞外检查点。在这里，我们报告了与未受影响的对照组相比，经组织学证实的代谢相关脂肪性肝炎 （MASH） 或肝纤维化患者表现出循环 ACBP/DBI 蛋白水平升高。血浆 ACBP/DBI 与患者的 NAFLD 和 FIB4 评分密切相关，这些相关性与年龄和体重指数无关。我们在几种小鼠模型中研究了单克隆抗体 （mAb） 中和小鼠 ACBP/DBI 对抗活动性肝病的能力，其中脂肪性肝炎是由四种不同的方案诱导的，即 （i） 蛋氨酸/胆碱缺乏饮食，（ii） 单独的西式饮食 （WD），（iii） WD 联合肝毒性剂 CCl₄，和 （iv） CCl₄ 的组合注射和口服乙醇激发试验。在这四种模型中，注射抗 ACBP/DBI mAb 减轻了肝损伤的组织学、酶学、代谢组学和转录组学体征，从而阻止或减少了非酒精性和酒精性肝病的进展。脂肪变性、炎症、气球样变和纤维化在临床前水平对 ACBP/DBI 抑制有反应。总而言之，这些发现支持 ACBP/DBI 在 MASH 和肝纤维化中的因果作用，以及治疗靶向 ACBP/DBI 的可能性。