University of Massachusetts Medical School Faculty Publications

Title

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

UMMS Affiliation

Department of Medicine, Division of Gastroenterology; UMass Metabolic Network; Graduate School of Biomedical Sciences, Translational Science Program

Publication Date

7-1-2016

Document Type

Article

Disciplines

Digestive System Diseases | Gastroenterology | Hepatology

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 article, 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 3-day alcohol binge was administered to C57BL/6 female mice, and features of alcoholic liver disease were assessed. Some mice were treated daily with intraperitoneal injections of a SYK inhibitor (R406; 5 to 10 mg/kg body weight) or drug vehicle control. Liver and serum samples were collected and were assessed by Western blotting, biochemical, ELISA, electrophoretic mobility shift assays, real-time quantitative polymerase chain reaction, and histopathological analysis.

RESULTS: We found that binge drinking induced significant SYK activation (SYK(Y525/526) ) 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-nuclear factor kappa beta (NF-kappaB) p65, NF-kappaB nuclear binding, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 mRNA in the liver. Compared to vehicle controls, SYK inhibitor treatment decreased alcohol binge-induced hepatocyte injury indicated by histology and serum alanine aminotransferase. Strikingly, SYK inhibitor treatment also resulted in a significant reduction in alcohol-induced liver steatosis.

CONCLUSIONS: 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.

Rights and Permissions

Citation: Alcohol Clin Exp Res. 2016 Jul;40(7):1524-30. doi: 10.1111/acer.13096. Epub 2016 May 14. Link to article on publisher's site

Comments

Co-author Arvin Aracheta-Vellve is a doctoral student in the Translational Science Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to Article in PubMed

Keywords

Alcoholic Hepatitis, Binge Drinking, Nonreceptor Tyrosine Kinase

Journal/Book/Conference Title

Alcoholism, clinical and experimental research

PubMed ID

27177528