A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques-猫眼课题宝

DOI：

10.1126/scitranslmed.abg8116

发表时间：

2021-12

期刊：

Science Translational Medicine

影响因子：

17.1

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Xiao-Jing Zhang;Yan‐Xiao Ji;Xu Cheng;Yanjie Cheng;Hailong Yang;Junyong Wang;Ling‐Ping Zhao;Yong-Ping Huang;Dating Sun;Hui Xiang;L. Shen;Peng-Long Li;Jun-Peng Ma;Rui-Feng Tian;Juan Yang;Xinxin Yao;Haibo Xu;Rufang Liao;Li Xiao;Peng Zhang;Xin Zhang;Guang-Nian Zhao;Xi Wang;Manli Hu;S. Tian;Juan Wan;Jingjing Cai;Xinliang Ma;Qingbo Xu;Yibin Wang;R. Touyz;Peter P. Liu;R. Loomba;Zhi‐Gang She;Hongliang Li

描述IMA-1靶向ALOX 12-ACC 1相互作用以预防和治疗NASH而不诱导高脂血症。停止肝细胞脂毒性的驱动因素尽管非酒精性脂肪性肝炎（NASH）的患病率和严重性，但仍然缺乏治疗方法。Zhang等人表明，脂氧合酶ALOX 12通过稳定ACC 1、改变溶酶体降解、增加肝细胞炎症和阻碍生酮来增加小鼠、猪和猕猴中NASH的严重程度，而不依赖于其酶功能。在另一份手稿中，Zhang等人证明，一种小分子有效地破坏了体内ALOX 12-ACC 1相互作用，阻止了NASH小鼠和猕猴模型中肝脏脂肪变性、炎症和纤维化的发展，而不会引发通常由抑制ACC 1的更典型的酶功能引起的高脂血症。非酒精性脂肪性肝炎（NASH）是一种进行性肝病，在美国已成为肝移植的主要指征。NASH的有效疗法的开发是一个主要的未满足的需求。在这里，我们确定了一种小分子IMA-1，可以通过中断花生四烯酸12-脂氧合酶（ALOX 12）-乙酰辅酶A羧化酶1（ACC 1）相互作用来治疗NASH。在雄性小鼠和食蟹猴治疗模型中，IMA-1显著阻断饮食诱导的NASH进展。在两个物种中，IMA-1的抗NASH功效与ACC抑制剂相当。蛋白质对接模拟和随后的功能实验表明，IMA-1的抗NASH作用在很大程度上依赖于其直接结合到ALOX 12中邻近其ACC 1相互作用表面的口袋，而不是抑制ALOX 12脂氧合酶活性。IMA-1治疗在小鼠和猕猴中均未引起高脂血症，这是直接抑制ACC酶活性的已知副作用。这些发现为使用基于小分子的NASH疗法提供了跨多个物种的概念证据。

Description IMA-1 targets the ALOX12-ACC1 interaction to both prevent and treat NASH without inducing hyperlipidemia. Halting a driver of hepatocyte lipotoxicity Despite its prevalence and seriousness, nonalcoholic steatohepatitis (NASH) still lacks a treatment. Zhang et al. show that the lipoxygenase ALOX12 increased NASH severity in mice, pigs, and macaques independent of its enzymatic function by stabilizing ACC1, altering lysosomal degradation, increasing hepatocyte inflammation, and impeding ketogenesis. In a separate manuscript, Zhang et al. demonstrate that a small molecule effectively disrupted the ALOX12-ACC1 interaction in vivo, halting the development of liver steatosis, inflammation, and fibrosis in mice and macaque models of NASH without eliciting the hyperlipidemia that typically results from inhibiting the more canonical enzymatic function of ACC1. Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques

文献摘要

相似文献