Differential Role Of Prkcε In The Pathogenesis Of Chronic Alcohol-Induced Liver Injury
Chronic alcohol consumption is a major cause of liver injury, progressing from hepatic steatosis to inflammation, necrosis, and fibrosis. Protein kinase C epsilon (PRKCε) has been implicated in alcohol-induced hepatic steatosis; however, its contribution to subsequent inflammatory and necrotic injury remains unclear. The present study investigated the differential role of PRKCε in chronic ethanol-induced liver injury using an experimental animal model. Mice were maintained on a high-fat diet and treated with either saline or PRKCε antisense oligonucleotides (ASO) for four weeks, followed by ethanol exposure. Hepatic lipid accumulation, fatty acid synthase (FAS), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), inflammation, necrosis, and fibrin deposition were evaluated. PRKCε ASO treatment significantly attenuated ethanol-induced hepatic lipid accumulation and prevented the ethanol-mediated increase in FAS expression. Furthermore, PRKCε inhibition completely suppressed the elevation of TNF-α expression associated with ethanol exposure. Despite these effects, PRKCε ASO administration did not significantly reduce chronic ethanol-induced hepatic inflammation or necrosis. Similarly, the ethanol-induced upregulation of PAI-1 and accumulation of fibrin were unaffected by PRKCε inhibition. These findings indicate that PRKCε plays an important role in alcohol-induced hepatic steatosis and associated metabolic alterations but is not the primary mediator of chronic inflammatory and necrotic liver injury. The persistence of PAI-1 elevation and fibrin deposition despite PRKCε inhibition suggests that these pathways may independently contribute to progression of alcohol-induced hepatic damage. Thus, targeting multiple pathological pathways may provide a more effective strategy for preventing chronic alcohol-related liver injury.