The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells.
Chronic ethanol consumption can result in hepatic fibrosis and cirrhosis. In addition to oxidative metabolism, ethanol can be metabolized by esterification with fatty acids to form fatty acid ethyl esters (FAEE) such as linolenic acid ethyl ester (LAEE). We have previously demonstrated that LAEE has promitogeinc and activating effects on hepatic stellate cells (HSC), but the mechanisms of these actions are not known. Intracellular signaling through MAP kinase pathways, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) can influence the activity of the transcription factor AP-1, while cell-cycle regulatory proteins such as cyclin E and cyclin-dependent kinase (CDK), play an important role in cell proliferation. In this study, we demonstrate that treatment of HSC with LAEE increases cyclin E expression and cyclin E/CDK2 activity, which may underlie the promitogenic effects of this compound. In addition, LAEE increases ERK and JNK activity, and these pathways play an important role in the activation of AP-1-dependent gene expression by LAEE. The stimulation of intracellular signaling pathways in HSC by this well-characterized ethanol metabolite may contribute to ethanol-induced hepatic fibrogenesis.
Li
Jianjun
J
Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858-4354, USA. lichixin@yahoo.com
Hu
Weimin
W
Baldassare
Joseph J
JJ
Bora
Puran S
PS
Chen
Shuang
S
Poulos
John E
JE
O'Neill
Rosemary
R
Britton
Robert S
RS
Bacon
Bruce R
BR
D000818:Animals; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D007728:Kupffer Cells / Q000187:drug effects* / Q000201:enzymology; D008042:Linolenic Acids / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019927:Cyclin E; D008042:Linolenic Acids; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C039896:ethyl linolenate