Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice

Abstract

Background Binge drinking is increasingly recognized as an important cause of liver disease with limited therapeutic options for patients. Binge alcohol use, similar to chronic alcohol consumption, induces numerous deregulated signaling events that drive liver damage, steatosis and inflammation. In this report, we evaluated the role of spleen tyrosine kinase (SYK), which modulates numerous signaling events previously identified linked in the development alcohol-induced liver pathology. Methods A three day alcohol binge was administered to C57BL/6 female mice and features of alcoholic liver disease (ALD) were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406) [5–10mg/kg body weight] or drug vehicle control. Liver and serum samples were collected and were assessed by western blotting, biochemical, ELISA, EMSA, RT-qPCR and histopathological analysis. Results We found that binge drinking induced significant SYK activation (SYKY525/526) with no change in total SYK expression in the liver. Functional inhibition of SYK activation using a potent SYK inhibitor, R406, was associated with a significant decrease in alcohol-induced hepatic inflammation as demonstrated by decreased phospho-NF-κB p65, NF-κB nuclear binding, TNF-α and MCP1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum ALT. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol induced liver steatosis. Conclusion Our novel observations demonstrate the role of SYK activation in the pathomechanism of binge drinking induced liver disease highlighting SYK a potential multifaceted therapeutic target.

Over expression of proteins that alter the intracellular signaling pathways in the cytoplasm of the liver cells forming Mallory-Denk bodies

“…It also played a modulating role in immune cell-driven liver inflammation, and hepatocyte cell death at different stages of ALD. Inhibition of SYK activation in the mouse model abrogated alcohol-induced neutrophil infiltration, resident immune cell and inflammasome activation, ERK1/2 mediated NFκB activation and IRF3-mediated apoptosis (Bukong et al, 2016a). It has recently been shown that STING and IRF3 modulate hepatocyte cell death during ALD, thereby, linking ER stress signaling with the mitochondrial pathway.…”

FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice

“…( ) Confirming and extending these results, our data show that in both models of ethanol‐induced liver injury, and in particular in the prolonged model in which steatosis is greater, treatment with all BA receptor agonists tested reduces ethanol‐induced FASN protein expression, providing an explanation for the beneficial effects of FXR and TGR5 activation on ALD‐induced liver pathology. ( )…”

“…(43) Confirming and extending these results, our data show that in both models of ethanol-induced liver injury, and in particular in the prolonged model in which steatosis is greater, treatment with all BA receptor agonists tested reduces ethanol-induced FASN protein expression, providing an explanation for the beneficial effects of FXR and TGR5 activation on ALD-induced liver pathology. (30,31) Pathogen-associated molecular patterns from bacterial fragments drive TLR4-mediated inflammation. (44) Specifically relevant to ALD is the NLRP3inflammasome, a multiprotein complex primed through TLR4 signaling and activated by release of endogenous damage-associated molecular patterns, such as hepatocyte-derived ATP and uric acid.…”

Using Zebrafish to Model Liver Diseases-Where Do We Stand?

“…Binge alcohol exposure causes liver inflammation, steatosis, hepatocyte death, and promotes activation of hepatic stellate cells and fibrogenesis [56]. Thus it is crucial to identify therapeutic agents that target multiple aspects of the disease.…”