Date of Award
Doctor of Philosophy (PhD)
Alcohol-associated liver disease (AALD) is an umbrella term for a spectrum of diseases resulting from chronic alcohol (e.g. ethanol) abuse ranging in severity from reversible conditions such as alcohol-induced steatosis to advanced and largely irreversible liver pathologies including alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). AALD is one of the primary causes of chronic liver disease worldwide and accounts for 44% of liver disease deaths in the United States. Drinking rates, both in the United States and globally, have increased year over year for the past three decades, a trend which has resulted in significantly increased incidences of AALD. Despite the progress in the AALD field, the molecular mechanisms governing the progression from reversible forms of AALD to more advanced stages are still poorly characterized. Aside from alcohol abstinence and liver transplantation, there are currently no effective FDA-approved pharmacological or nutritional therapies for treating patients with AALD. Consequently, understanding the underlying molecular mechanisms of AALD pathogenesis may lead to novel therapeutic strategies that are desperately needed.
ABL1 and ABL2 are highly conserved non-receptor tyrosine kinases which participate in a diverse set of cellular functions including mitosis, adhesion, differentiation, and stress response. While sharing similar structures and substrates, ABL1 and ABL2 are functionally redundant but individually necessary to normal development and homeostasis. The ABL kinases have been implicated in a number of liver pathologies, including ischemia/reperfusion injury, hepatic fibrosis, NAFLD, and HCC, suggesting a central role for this family of proteins in liver disease pathogenesis. However, despite the fact that activated ABL kinases have been shown to directly interact with molecules implicated in hepatocyte and stellate cell response to alcohol and oxidative stress, the roles of the ABL kinases in AALD have never been explored.
To this end, we sought to investigate the contributions of the ABL kinases in murine models of alcoholism and discovered alcohol feeding results in significant activation of ABL1 and ABL2 in the liver. Analysis of liver tissue from healthy donors and AH patients also revealed significant activation of the ABL kinases, suggesting a potential role in AALD pathogenesis. To further characterize the potential roles of the ABL kinases in AALD, we generated transgenic hepatocyte-specific knockouts of Abl1 and Abl2 and subjected them to alcohol treatment. Interestingly, the hepatic deletion of Abl2 ameliorated liver injury and steatosis when compared to wild-type alcohol-fed mice. Gene set enrichment analyses revealed significant down regulation of PPAR signaling which was further confirmed using an in vitro system of hepatocyte alcohol exposure. Affirming our in vivo findings, we discovered that both genetic and pharmacologic inhibition of ABL2 attenuates alcohol-induced steatosis in a PPAR gamma-dependent manner. We further determined that alcohol-induced PPAR gamma may be regulated by HIF1 alpha, a master regulator of hypoxic response, in an ABL2-dependent manner.
To our knowledge, this is the first direct assessment of the ABL kinases in AALD and the first to demonstrate functional relationships between ABL2 and PPAR gamma as well as ABL2 and HIF1 alpha. Our data suggest ABL2 represents a novel and promising target for AALD treatment, potentially providing a much needed therapeutic option for this often forgotten patient population.
Malnassy, Gregory, "ABL2 Promotes Alcohol-Associated Liver Disease via PPAR Gamma Regulation" (2022). Dissertations. 3934.
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Copyright © 2022 Gregory Malnassy
Available for download on Wednesday, January 17, 2024