Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 254, Issue 1-2, Pages 37-46Publisher
KLUWER ACADEMIC PUBL
DOI: 10.1023/A:1027356412399
Keywords
pentoxifylline; retinol; phospholipase A(2); arachidonic acid; prostaglandin; neutral lipid; hepatic stellate cell
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In liver fibrosis, the quiescent hepatic stellate cells (HSC) are activated to proliferate and express the activated myofibroblast phenotype, losing fat droplets and the stored vitamin A, and depositing more extracellular matrix. Therapeutic strategies for liver fibrosis are focused on HSC. Pentoxifylline (PTF), an analog of the methylxanthine, prevents the biochemical and histological changes associated with animal liver fibrosis. The aim of the present study was to investigate the phenotypic change of myofibroblasts into quiescent lipocytes by PTF and/or retinol, using a permanent cell line GRX that represents murine HSC. We studied the action of both drugs on the synthesis of neutral lipids, activity of phospholipase A(2) (PLA(2)), release of arachidonic acid (AA) and prostaglandins synthesis. Accumulation and synthesis of neutral lipids was dependent upon association of retinol with PTF. PTF (0.5 mg/mL) alone did not induce lipid accumulation and synthesis, but in cells induced by physiologic concentration of retinol (1-2.5 muM), it increased the quantity of stored lipids. Retinol and PTF (5 muM and 0.1 mg/mL, respectively) had a synergistic effect on neutral lipid synthesis and accumulation. In higher PTF concentrations (0.5 and 0.7 mg/ml), the synthesis was stimulated but accumulation decreased. Membrane-associated PLA(2) activity decreased after PTF treatment, which increased the AA release 8 fold, and significantly increased the production of PGE(2), but not of PGF(2a). However, when in presence of retinol, we observed a slightly higher increase in PGE(2) and PGF(2a) production. In conclusion, PTF treatment generated an excess of free AA. We propose that retinol counteracts the action of PTF on the AA release and PGs production, even though both drugs stimulated the lipocyte induction in the HSC.
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