Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis-猫眼课题宝

DOI：

10.1126/scitranslmed.abg8117

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;Zhi‐Gang She;Junyong Wang;Dating Sun;L. Shen;H. Xiang;Xu Cheng;Yan‐Xiao Ji;Yong-Ping Huang;Peng-Long Li;Xia Yang;Yanjie Cheng;Jun-Peng Ma;Haiping Wang;Yufeng Hu;Fengjiao Hu;S. Tian;Han Tian;Peng Zhang;Guang-Nian Zhao;Lin Wang;Manli Hu;Qin Yang;Lihua Zhu;Jingjing Cai;Juan Yang;Xin Zhang;Xinliang Ma;Qingbo Xu;R. Touyz;Peter P. Liu;R. Loomba;Yibin Wang;Hongliang Li

描述ALOX12通过抑制多个物种的ACC1溶酶体降解来驱动NASH。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。脂毒性是公认的非酒精性脂肪性肝炎（NASH）的病理触发因素和加速因素。然而，脂毒性诱导的NASH的分子基础仍然难以捉摸。在这里，我们系统地绘制了肝脏转录组景观的变化，以应对跨多个物种的脂毒性损伤。花生四烯酸途径，特别是花生四烯酸12-脂氧合酶（ALOX 12）基因的保守和稳健激活与人类、患有自发性NASH的猕猴以及猪和小鼠饮食NASH模型中的NASH严重程度密切相关。使用功能获得和功能丧失研究，我们发现ALOX 12在小鼠和巴马猪模型中均显著加重NASH。ALOX 12显示通过溶酶体降解机制直接靶向乙酰辅酶A羧化酶1（ACC1）诱导NASH。总的来说，我们的研究结果揭示了NASH发病机制的关键分子驱动因素，并表明ALOX12-ACC1相互作用可能是NASH的治疗靶点。

Description ALOX12 drives NASH by inhibiting ACC1 lysosomal degradation across multiple species. 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. Lipotoxicity is a recognized pathological trigger and accelerator of nonalcoholic steatohepatitis (NASH). However, the molecular basis of lipotoxicity-induced NASH remains elusive. Here, we systematically mapped the changes in hepatic transcriptomic landscapes in response to lipotoxic insults across multiple species. Conserved and robust activation of the arachidonic acid pathway, in particular the arachidonate 12-lipoxygenase (ALOX12) gene, was closely correlated with NASH severity in humans, macaques with spontaneously developed NASH, as well as swine and mouse dietary NASH models. Using gain- and loss-of-function studies, we found that ALOX12 markedly exacerbated NASH in both mice and Bama pig models. ALOX12 was shown to induce NASH by directly targeting acetyl-CoA carboxylase 1 (ACC1) via a lysosomal degradation mechanism. Overall, our findings reveal a key molecular driver of NASH pathogenesis and suggest that ALOX12-ACC1 interaction may be a therapeutic target in NASH.

Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis

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