Title : The role of ABL kinases in alcohol-associated liver disease
Abstract:
Alcohol-asscociated liver disease (ALD) represents a spectrum of alcohol use-related diseases, ranging from steatosis to cirrhosis, and is one of the primary causes of chronic liver disease worldwide. 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, including mitosis, adhesion, differentiation, and stress response. We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well liver tissues from mice subjected to an alcohol feeding regimen. To further our understanding of the role of the ABL kinases in ALD, we established strains of liver-specific ABL1 and ABL2 knockout mice. When subjected to alcohol feeding, we found that knockout of ABL2, but not ABL1, abrogated alcohol-induced steatosis. 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 PPARg, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in ABL2 knockout mice, suggesting a potentially novel role for ABL2 in the regulation of PPARg. In vitro analyses conducted in HepG2, an immortalized liver cell line, revealed that PPARg protein levels increase in response to alcohol treatment leading to marked increases in lipid accumulation as determined by Oil Red O staining. shRNA-mediated knockdown of ABL2, however, abolished the alcohol-induced accumulation of PPARg as well as subsequent lipid accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARg protein expression. Furthermore, treatment with GMB475, a recently developed, highly specific proteolysis-targeting chimera (PROTAC) directed against the ABL kinases, attenuated alcohol-induced PPARg protein accumulation as well as subsequent lipid droplet formation. Based on our current evidence, we conclude that alcohol-induced ABL2 activation promotes ALD through increasing PPARg expression, and ABL2 inhibition may serve as a promising target for the treatment of ALD.
