PKCε Contributes to Chronic Ethanol-Induced Steatosis in Mice but not Inflammation and Necrosis
Article first published online: 31 JAN 2014
Copyright © 2014 by the Research Society on Alcoholism.
Alcoholism: Clinical and Experimental Research
Volume 38, Issue 3, pages 801–809, March 2014
How to Cite
Kaiser, J. P., Guo, L., Beier, J. I., Zhang, J., Bhatnagar, A. and Arteel, G. E. (2014), PKCε Contributes to Chronic Ethanol-Induced Steatosis in Mice but not Inflammation and Necrosis. Alcoholism: Clinical and Experimental Research, 38: 801–809. doi: 10.1111/acer.12324
- Issue published online: 15 MAR 2014
- Article first published online: 31 JAN 2014
- Manuscript Accepted: 24 SEP 2013
- Manuscript Received: 31 JAN 2013
- National Institute of Alcohol Abuse and Alcoholism. Grant Numbers: AA003624, AA017346
- National Institute of Environmental Health Sciences. Grant Number: ES11860
- Alcoholic Liver Disease;
- Protein Kinase C
Protein kinase C epsilon (PKCε) has been shown to play a role in experimental steatosis by acute alcohol. The “two-hit” hypothesis implies that preventing steatosis should blunt more advanced liver damage (e.g., inflammation and necrosis). However, the role of PKCε in these pathologies is not yet known. The goal of this current work was to address this question in a model of chronic alcohol exposure using antisense oligonucleotides (ASO) against PKCε.
Accordingly, PKCε ASO- and saline-treated mice were fed high-fat control or ethanol (EtOH)-containing enteral diets for 4 weeks.
Chronic EtOH exposure significantly elevated hepatic lipid pools as well as activated PKCε. The PKCε ASO partially blunted the increases in hepatic lipids caused by EtOH. Administration of PKCε ASO also completely prevented the increase in the expression of fatty acid synthase, and tumor necrosis factor α caused by EtOH. Despite these protective effects, the PKCε ASO was unable to prevent the increases in inflammation and necrosis caused by chronic EtOH. These latter results correlated with an inability of the PKCε ASO to blunt the up-regulation of plasminogen activator inhibitor-1 (PAI-1) and the accumulation of fibrin. Importantly, PAI-1 has been previously shown to more robustly mediate inflammation and necrosis (vs. steatosis) after chronic EtOH exposure.
This study identifies a novel potential mechanism where EtOH, independent of steatosis, can contribute to liver damage. These results also suggest that PAI-1 and fibrin accumulation may be at the center of this PKCε-independent pathway.