SELECTIVE MODIFICATION OF RAT HEPATIC-MICROSOMAL FATTY-ACID CHAIN ELONGATION AND DESATURATION BY FIBRATES - RELATIONSHIP WITH PEROXISOME PROLIFERATION

1 The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-, palmitol eoyl- and gamma-linolenoyl-CoA elongase, Delta-9, Delta-6 and Delta-5 desaturase activities, and microsomal electron transport chains, as we ll as the correlation with the peroxisomal proliferation phenomenon ha ve been studied in male Sprague-Dawley rats. 2 As reported in our prev ious work, the three drugs behave as peroxisomal proliferators (the or der of potency was BFB>CFB greater than or equal to GFB) and induced a clear reduction in both plasma cholesterol and triglyceride levels. 3 Palmitoyl-CoA elongation activity was increased by the three drugs (B FB = GFB>CFB), whereas palmitoleoyl-CoA elongation activity was only e nhanced by GFB. Elongation activity was not modified by fibrates when gamma-linolenoyl-CoA was used as substrate. These results are in accor dance with the existence of three different elongation systems for sat urated, mono- and polyunsaturated fatty acids. 4 Delta-9, Delta-6 and Delta-5 desaturase activities were increased by the three fibrates, wi th an order of potency BFB>CFB = GFB for Delta-9 and Delta-5, and GFB> BFB = CFB for Delta-6. 5 Of the enzyme activities integrated in the mi crosomal electron transport chains, NADH cytochrome bg reductase was n ot affected by fibrate treatment, NADPH cytochrome c reductase activit y was enhanced (BFB = GFB>CFB), whereas NADH cytochrome c reductase ac tivity was reduced by CFB and BFB. 6 The increase in Delta-9 and Delta -5 desaturase activities was highly dependent on the peroxisomal proli feration phenomena, whereas the increase in Delta-6 desaturase activit y and the decrease in NADH cytochrome c reductase was mainly independe nt. The modifications of palmitoyl-CoA elongase and NADPH cytochrome c reductase activities, as well as plasma lipid levels, were partially correlated with peroxisomal beta-oxidation, but the r(2) values obtain ed point to the existence of additional independent mechanisms. 7 As m an is assumed to be a species refractory to peroxisomal proliferation, only those fibrate effects not absolutely related to this phenomenon are expected to appear after fibrate therapy.