DLPC and SAMe prevent alpha1(I) collagen mRNA up-regulation in human hepatic stellate cells, whether caused by leptin or menadione.
We previously reported that the combination of dilinoleoylphosphatidylcholine (DLPC) and S-adenosylmethionine (SAMe), which have antioxidant properties and antifibrogenic actions, prevented leptin-stimulated tissue inhibitor of metalloproteinase (TIMP)-1 production in hepatic stellate cells (HSCs) by inhibiting H2O2-mediated signal transduction. We now show that DLPC and SAMe inhibit alpha1(I) collagen mRNA expression induced by leptin or menadione in LX-2 human HSCs. We found that DLPC and SAMe prevent H2O2 generation and restore reduced glutathione (GSH) depletion whether caused by leptin or menadione. Blocking H2O2 signaling through ERK1/2 and p38 pathways resulted in a complete inhibition of leptin or menadione-induced alpha1(I) collagen mRNA. The inhibition of collagen mRNA by DLPC and SAMe combined is at least two times more effective than that by DLPC or SAMe alone. In conjunction with the prevention of TIMP-1 production, the ability of DLPC and SAMe to inhibit alpha1(I) collagen mRNA expression provides a mechanistic basis for these innocuous compounds in the prevention of hepatic fibrosis, because enhanced TIMP-1 and collagen productions are associated with hepatic fibrogenesis and their attenuation may diminish fibrosis.
Cao
Qi
Q
Alcohol Research and Treatment Center, James J. Peters Veterans Affairs Medical Center, 130 W. Kingsbridge Road, Bronx, NY 10468, USA.
Mak
Ki M
KM
Lieber
Charles S
CS
D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010713:Phosphatidylcholines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D024483:Vitamin K 3 / Q000494:pharmacology*
C508476:1,2-dilinolenoylphosphatidylcholine; D024042:Collagen Type I; D020738:Leptin; D010713:Phosphatidylcholines; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D024483:Vitamin K 3; D012436:S-Adenosylmethionine; D006861:Hydrogen Peroxide; D002374:Catalase; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione