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-, palmitoleoyl- and gamma-linolenoyl-CoA elongase, Delta-9, Delta-6 and Delta-5 desaturase activities, and microsomal electron transport chains, as well as the correlation with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2 As reported in our previous work, the three drugs behave as peroxisomal proliferators (the order 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 (BFB = GFB>CFB), whereas palmitoleoyl-CoA elongation activity was only enhanced by GFB. Elongation activity was not modified by fibrates when gamma-linolenoyl-CoA was used as substrate. These results are in accordance with the existence of three different elongation systems for saturated, mono- and polyunsaturated fatty acids. 4 Delta-9, Delta-6 and Delta-5 desaturase activities were increased by the three fibrates, with 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 microsomal electron transport chains, NADH cytochrome bg reductase was not affected by fibrate treatment, NADPH cytochrome c reductase activity was enhanced (BFB = GFB>CFB), whereas NADH cytochrome c reductase activity was reduced by CFB and BFB. 6 The increase in Delta-9 and Delta-5 desaturase activities was highly dependent on the peroxisomal proliferation phenomena, whereas the increase in Delta-6 desaturase activity and the decrease in NADH cytochrome c reductase was mainly independent. 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 obtained point to the existence of additional independent mechanisms. 7 As man 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.