PKCε Contributes to Chronic Ethanol‐Induced Steatosis in Mice but not Inflammation and Necrosis

Alcoholic liver disease (ALD) is a serious concern for the world’s population, causing millions of deaths per year (Grant et al., 1988). Whereas the pathological steps of ALD are well understood, our knowledge of the mechanisms involved in causing the disease is lacking; as a result, there is no FDA-approved therapy to treat or reverse ALD. Steatosis is a critical stage in the pathology of alcoholic liver disease. Although steatosis was once thought to be an benign pathology of ALD, more recent evidence has indicated that blunting or blocking steatosis could help prevent the progression of ALD (Teli et al., 1995; Day and James 1998). Therefore, pharmacologically targeting the cause(s) of ethanol-induced steatosis is potentially a promising therapy for ALD. Recent evidence has suggested that protein kinases c-e (PKCe), can contribute to steatosis in experimental non-alcoholic fatty liver disease (NAFLD) (Samuel et al., 2004). Work from this group showed that PKCe also plays a causal role in acute ethanol-induced steatosis in mice (Kaiser et al., 2009). Results from that study support the working hypothesis that the inhibition of β-oxidation of fatty acids caused by ethanol metabolism increases the fatty acid supply for diacylglycerol (DAG) synthesis. This increase in DAG allosterically activates PKCe, which then contributes to the increase in hepatic triglycerides caused by ethanol by inducing insulin resistance (Kaiser et al., 2009). Thus, PKCe activation may be a shared mechanism of hepatic steatosis in ALD and NAFLD. Whereas acute bolus ethanol causes a robust steatotic response in the liver (Kaiser et al., 2009), there is little or no inflammation or necrosis caused by this dose regimen of ethanol in rodents. PKCe has been shown to contribute to inflammation in response to various insults (e.g. LPS), which suggests that PKCe may also contribute to more advanced stages of ALD (e.g. steatohepatitis) (Aksoy et al., 2004). Furthermore, as mentioned above, blunting steatosis caused by alcohol may in and of itself prevent later phases of ALD. This potential role of PKCe in these later stages of experimental ALD has not yet been directly studied. Therefore, the purpose of this study was to determine the role of PKCe in chronic ethanol-induced liver damage.