Inhibition of Abelson Tyrosine-Protein Kinase 2 Suppresses the Development of Alcohol-associated liver disease by Decreasing PPARgamma Expression.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) represents a spectrum of alcohol use-related liver diseases. Outside of alcohol abstinence, there are currently no FDA-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions. We investigated the role of the ABL kinases in alcohol-associated liver disease.

METHODS: We utilized samples from patients with ALD compared to healthy controls to elucidate a clinical phenotype. We established strains of liver-specific Abl1 and Abl2 knockout mice and subjected them to the NIAAA acute-on-chronic alcohol feeding regimen. Murine samples were subjected to RNA-sequencing, AST, Oil Red O staining, H&E staining, western blotting, and qPCR to assess phenotypic changes following alcohol feeding. In vitro modeling in HepG2 cells as well as primary hepatocytes from C57BL6/J mice was used establish this mechanistic link of ALD pathogenesis.

RESULTS: We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well as in liver tissues from mice subjected to an alcohol feeding regimen. We found that the liver-specific knockout of Abl2, but not Abl1, attenuated alcohol-induced steatosis, liver injury, and inflammation. Subsequent RNA-sequencing and gene set enrichment analyses of mouse liver tissues revealed that, relative to wild-type alcohol-fed mice, Abl2 knockout alcohol-fed mice exhibited numerous pathway changes, including significantly decreased PPAR signaling. Further examination revealed that PPARγ, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in Abl2 knockout mice. In vitro analyses revealed that shRNA-mediated knockdown of ABL2 abolished the alcohol-induced accumulation of PPARγ as well as subsequent lipid accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARγ protein expression. Further, we demonstrated that the regulation of HIF1α by ABL2 is required for alcohol-induced PPARγ expression. Furthermore, treatment with ABL kinase inhibitors attenuated alcohol-induced PPARγ expression, lipid droplet formation and liver injury.

CONCLUSIONS: Based on our current evidence, we propose that alcohol-induced-ABL2 activation promotes ALD through increasing HIF1α and the subsequent PPARγ expression, and ABL2 inhibition may serve as a promising target for the treatment of ALD.