Up regulation of Spleen Tyrosine Kinase in ballooned hepatocytes with Mallory‐Denk Bodies in Alcoholic Liver Disease

Abstract

Liver injury from alcohol abuse causes balloon hepatocytes and MDB formation. Mallory‐Denk bodies (MDBs) are found in 70% to 75% of patients with alcoholic hepatitis (AH). MDBs are composed of intracellular aggregations of misfolded proteins in ballooned hepatocytes. To determine the mechanism of balloon degeneration and MDB formation in hepatocytes, we evaluated the role of spleen tyrosine kinase (Syk) which is associated with transmembrane receptors to mediate numerous signal transductions downstream of these receptors. Spleen tyrosine kinase is widely expressed in hematopoietic cells and modulates several signaling pathways including PIK3/AKT and p7056 pathways. These pathways are important in regulating the cell cycle and are actively involved in mediating cell adhesion. Dysregulation of the PI3K/Akt pathway is implicated in a number of human diseases including cancer, diabetes, cardiovascular disease and neurological diseases. In this study, liver biopsy sections fixed in formalin and embedded in paraffin (FFPE) were used from patients with alcoholic hepatitis (AH). The results show that the expression of Syk protein is up regulated by RNAseq and real time PCR analyses in the alcoholic hepatitis patients compared to controls. The results were also supported by using IHC fluorescent intensity staining morphometric system. Morphometric quantification of fluorescent intensity showed a two fold increase in Syk in the cells forming MDBs compared to surrounding normal hepatocytes. Interestingly, the upregulation of Syk protein is co‐localized with ubiquitinated proteins in the cytoplasm of balloon cell hepatocytes which have formed MDBs. This observation demonstrates the role of Syk as a potential multifunctional target in protein quality control mechanism of hepatocytes when ER stress is activated.