PKCepsilon plays a causal role in acute ethanol-induced steatosis.
Steatosis is a critical stage in the pathology of alcoholic liver disease (ALD), and preventing steatosis could protect against later stages of ALD. PKCepsilon has been shown to contribute to hepatic steatosis in experimental non-alcoholic fatty liver disease (NAFLD); however, the role of PKCepsilon in ethanol-induced steatosis has not been determined. The purpose of this study was to therefore test the hypothesis that PKCepsilon contributes to ethanol-induced steatosis. Accordingly, the effect of acute ethanol on indices of hepatic steatosis and insulin signaling were determined in PKCepsilon knockout mice and in wild-type mice that received an anti-sense oligonucleotide (ASO) to knockdown PKCepsilon expression. Acute ethanol (6g/kg i.g.) caused a robust increase in hepatic non-esterified free fatty acids (NEFA), which peaked 1h after ethanol exposure. This increase in NEFA was followed by elevated diacylglycerols (DAG), as well as by the concomitant activation of PKCepsilon. Acute ethanol also changed the expression of insulin-responsive genes (i.e. increased G6Pase, downregulated GK), in a pattern indicative of impaired insulin signaling. Acute ethanol exposure subsequently caused a robust increase in hepatic triglycerides. The accumulation of triglycerides caused by ethanol was blunted in ASO-treated or in PKCepsilon(-/-) mice. Taken together, these data suggest that the increase in NEFA caused by hepatic ethanol metabolism leads to an increase in DAG production via the triacylglycerol pathway. DAG then subsequently activates PKCepsilon, which then exacerbates hepatic lipid accumulation by inducing insulin resistance. These data also suggest that PKCepsilon plays a causal role in at least the early phases of ethanol-induced liver injury.
Kaiser
J Phillip
JP
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Beier
Juliane I
JI
Zhang
Jun
J
David Hoetker
J
J
von Montfort
Claudia
C
Guo
Luping
L
Zheng
Yuting
Y
Monia
Brett P
BP
Bhatnagar
Aruni
A
Arteel
Gavin E
GE
D000199:Actins / Q000235:genetics; D000818:Animals; D017931:DNA Primers; D000431:Ethanol / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced* / Q000201:enzymology; D005941:Glucokinase / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense; D051744:Protein Kinase C-epsilon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
D000199:Actins; D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014280:Triglycerides; D000431:Ethanol; D005941:Glucokinase; D051744:Protein Kinase C-epsilon