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PKC ε Contributes to Chronic Ethanol‐Induced Steatosis in Mice but not Inflammation and Necrosis
Author(s) -
Kaiser J. Phillip,
Guo Luping,
Beier Juliane I.,
Zhang Jun,
Bhatnagar Aruni,
Arteel Gavin E.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12324
Subject(s) - steatosis , protein kinase c , inflammation , tumor necrosis factor alpha , endocrinology , medicine , chemistry , plasminogen activator inhibitor 1 , plasminogen activator , necrosis , cancer research , kinase , biochemistry
Background Protein kinase C epsilon ( PKC ε ) 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 PKC ε 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 PKC ε . Methods Accordingly, PKC ε ASO ‐ and saline‐treated mice were fed high‐fat control or ethanol (EtOH)‐containing enteral diets for 4 weeks. Results Chronic EtOH exposure significantly elevated hepatic lipid pools as well as activated PKC ε . The PKC ε ASO partially blunted the increases in hepatic lipids caused by EtOH. Administration of PKC ε 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 PKC ε ASO was unable to prevent the increases in inflammation and necrosis caused by chronic EtOH. These latter results correlated with an inability of the PKC ε 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. Conclusions 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 PKC ε ‐independent pathway.