PKCε contributes to chronic ethanol-induced steatosis in mice but not inflammation and necrosis.
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.
Department of Pharmacology and Toxicology , University of Louisville Health Sciences Center, Louisville, Kentucky; University of Louisville Alcohol Research Center , Louisville, Kentucky.
J Phillip
JP
Kaiser
Luping
L
Guo
Juliane I
JI
Beier
Jun
J
Zhang
Aruni
A
Bhatnagar
Gavin E
GE
Arteel
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000652:urine; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects* / Q000652:urine; D005235:Fatty Liver, Alcoholic / Q000201:enzymology / Q000209:etiology*; D005337:Fibrin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006519:Hepatitis, Alcoholic / Q000209:etiology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D051744:Protein Kinase C-epsilon / Q000378:metabolism*
D015415:Biomarkers; D002492:Central Nervous System Depressants; D004075:Diglycerides; D000431:Ethanol; D005337:Fibrin; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon
Alcohol; Alcoholic Liver Disease; Inflammation; Protein Kinase C; Steatosis