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Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis

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.