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

Authors

  • J. Phillip Kaiser,

    1. Department of Pharmacology and Toxicology , University of Louisville Health Sciences Center, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center , Louisville, Kentucky
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  • Luping Guo,

    1. Department of Pharmacology and Toxicology , University of Louisville Health Sciences Center, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center , Louisville, Kentucky
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  • Juliane I. Beier,

    1. Department of Pharmacology and Toxicology , University of Louisville Health Sciences Center, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center , Louisville, Kentucky
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  • Jun Zhang,

    1. Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Aruni Bhatnagar,

    1. Department of Pharmacology and Toxicology , University of Louisville Health Sciences Center, Louisville, Kentucky
    2. Department of Medicine, Division of Cardiology, University of Louisville Health Sciences Center, Louisville, Kentucky
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  • Gavin E. Arteel

    Corresponding author
    1. Department of Pharmacology and Toxicology , University of Louisville Health Sciences Center, Louisville, Kentucky
    2. University of Louisville Alcohol Research Center , Louisville, Kentucky
    • Reprint requests: Gavin E. Arteel, PhD, Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, 505 South Hancock Street, CTRB, Room 552, Louisville, KY, 40292; Tel.: 502-852-5157; Fax: 502-852-3242; E-mail: gavin.arteel@louisville.edu

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Abstract

Background

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.

Methods

Accordingly, PKCε 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 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.

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 PKCε-independent pathway.

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