期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 624, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abg8117
关键词
-
资金
- National Science Foundation of China [81630011, 81970364, 81970070]
- Major Research Plan of the National Natural Science Foundation of China [91639304]
- National Key Research and Development Program of China Stem Cell and Translational Research [2016YFF0101504]
- Creative Groups Project of Hubei Province [2016CFA010]
- Hubei Science and Technology Support Project [2018BEC473]
- Hubei construction project of science and technology condition platform in Province [2017BEC001]
- scientific research project of Hubei Health Commission [WJ2019Q046]
Lipotoxicity plays a crucial role in the pathogenesis of NASH, with ALOX12 shown to exacerbate NASH severity by targeting ACC1, suggesting a potential therapeutic target.
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.
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