The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells.

Abstract

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.

• Authors: Jianjun Li, Weimin Hu, Joseph J Baldassare, Puran S Bora, Shuang Chen, John E Poulos, Rosemary O'Neill, Robert S Britton, Bruce R Bacon
• Journal: Life sciences (Life Sci) Vol. 73 Issue 9 Pg. 1083-96 (Jul 18 2003) ISSN: 0024-3205 [Print] Netherlands
• PMID: 12818718 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cdkn1b protein, rat
• Cell Cycle Proteins
• Cyclin E
• Linolenic Acids
• Transcription Factor AP-1
• Tumor Suppressor Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Protein Serine-Threonine Kinases
• CDC2-CDC28 Kinases
• Cdk2 protein, rat
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinases
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• ethyl linolenate

Topics

• Animals
• Blotting, Western
• CDC2-CDC28 Kinases
• Cell Cycle Proteins (metabolism)
• Cells, Cultured
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclin-Dependent Kinases (metabolism)
• Gene Expression Regulation (physiology)
• JNK Mitogen-Activated Protein Kinases
• Kupffer Cells (drug effects, enzymology)
• Linolenic Acids (pharmacology)
• Mitogen-Activated Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Rats
• Signal Transduction
• Transcription Factor AP-1 (genetics, metabolism)
• Transfection
• Tumor Suppressor Proteins (metabolism)