作者
Xiaojing Zhang,Zhi‐Gang She,Junyong Wang,Dating Sun,Lijun Shen,Hui Xiang,Xu Cheng,Yan‐Xiao Ji,Yaji Huang,Penglong Li,Xia Yang,Yun Cheng,Junpeng Ma,Haiping Wang,Yufeng Hu,Fengjiao Hu,Tian Shen,Han Tian,Peng Zhang,Guang‐Nian Zhao,Lin Wang,Manli Hu,Qin Yang,Lihua Zhu,Jingjing Cai,Juan Yang,Xin Zhang,Xin‐Liang Ma,Qingbo Xu,Rhian M. Touyz,Peter P. Liu,Rohit Loomba,Yibin Wang,Hongliang Li
摘要
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.