Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis.
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.
Duke Scholars
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- Swine
- Non-alcoholic Fatty Liver Disease
- Mice, Inbred C57BL
- Mice
- Liver Cirrhosis
- Liver
- Disease Models, Animal
- Animals
- 4003 Biomedical engineering
- 3206 Medical biotechnology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Swine
- Non-alcoholic Fatty Liver Disease
- Mice, Inbred C57BL
- Mice
- Liver Cirrhosis
- Liver
- Disease Models, Animal
- Animals
- 4003 Biomedical engineering
- 3206 Medical biotechnology