Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis.
Xiao-Jing ZhangZhi-Gang SheJunyong WangDating SunLi-Jun ShenHui XiangXu ChengYan-Xiao JiYong-Ping HuangPeng-Long LiXia YangYanjie ChengJun-Peng MaHai-Ping WangYufeng HuFengjiao HuSong TianHan TianPeng ZhangGuang-Nian ZhaoLin WangMan-Li HuQin YangLi-Hua ZhuJingjing CaiJuan YangXin ZhangXin-Liang MaQingbo XuRhian M TouyzPeter P LiuStephen CaldwellYibin WangHong Liang LiPublished in: Science translational medicine (2021)
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.