title: Dilinoleoylphosphatidylcholine prevents transforming growth factor-beta1-mediated collagen accumulation in cultured rat hepatic stellate cells.
abstract: Polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines, protects against alcoholic and nonalcoholic liver fibrosis in baboons and rats, respectively. In this study, we assessed the antifibrogenic action of dilinoleoylphosphatidylcholine (DLPC), the main phosphatidylcholine species of PPC, against transforming growth factor-beta1-mediated expression of alpha1(I) procollagen, tissue inhibitor of metallopreoteinase-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in cultured rat hepatic stellate cells (HSCs). In primary culture-activated HSCs, TGF-beta1 up-regulated the alpha1(I) procollagen mRNA level with a concomitant increase in type I collagen accumulation in culture media. Whereas TIMP-1 mRNA levels and TIMP-1 accumulation in media were also increased by TGF-beta1, MMP-13 mRNA expression and MMP-13 concentration in media were not altered. DLPC fully blocked TGF-beta1-induced increase in alpha1(I) procollagen mRNA expression and decreased collagen accumulation in media. Whereas TIMP-1 mRNA level and TIMP-1 accumulation in media were decreased by DLPC, MMP-13 mRNA expression and MMP-13 concentration in media were not changed by this treatment. Palmitoyl-linoleoylphosphatidylcholine (PLPC), the second most abundant component of PPC, had no effect on the concentrations of collagen, TIMP-1, and MMP-13 in HSC culture. We conclude that DLPC prevents TGF-beta1-mediated HSC fibrogenesis through down-regulation of alpha1(I) procollagen and TIMP-1 mRNA expression. The latter effect leads to a decreased accumulation of TIMP-1 that, in the presence of unchanged MMP-13 mRNA expression and MMP-13 concentration, results in a larger ratio of MMP-13/TIMP-1 concentrations in the culture media, favoring collagen degradation and lesser collagen accumulation. This effect of DLPC may explain, at least in part, the antifibrogenic action of PPC against alcoholic and other fibrotic disorders of the liver.
authors.affiliation: Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center, 130 W Kingsbridge Road, Bronx, NY 10468, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Ki M
authors.initials: KM
authors.lastname: Mak
authors.forename: Charles S
authors.initials: CS
authors.lastname: Lieber
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics*; D017364:Collagenases / Q000032:analysis / Q000235:genetics; D003893:Desmin / Q000032:analysis; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D008297:Male; D053509:Matrix Metalloproteinase 13; D010713:Phosphatidylcholines / Q000494:pharmacology*; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014746:Vimentin / Q000032:analysis
chemical_list: D000199:Actins; D024042:Collagen Type I; D003893:Desmin; D010713:Phosphatidylcholines; D011347:Procollagen; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C002448:1,2-linoleoylphosphatidylcholine; C055402:1-palmitoyl-2-linoleoylphosphatidylcholine; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat