DIFFERENT EFFECTS OF FIBRATES ON THE MICROSOMAL FATTY-ACID CHAIN ELONGATION AND THE ACYL COMPOSITION OF PHOSPHOLIPIDS IN GUINEA-PIGS

1 The effects in vitro and in vivo of three fibric acid derivatives, c lofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on some enzym e activities related to fatty acid biosynthesis, namely palmitoyl-CoA synthetase and hydrolases (microsomal and cytosolic), NADH and NADPH c ytochrome c reductases and acyl-CoA elongases were investigated in gui nea-pigs. 2 The three fibrates inhibited acyl-CoA elongation in vitro, irrespective of the substrate of elongation used (saturated, monounsa turated, polyunsaturated) and with an order of potency GFB>BFB>CFB. In the case of GFB, inhibition occured at concentrations that can be rea ched in vivo. 3 Microsomal palmitoyl-CoA hydrolase and synthetase were also inhibited in vitro (GFB greater than or equal to BFB>CFB), where as NADH cytochrome c reductase activity was increased by GFB. Neverthe less, the magnitude of changes were lower than those observed in elong ation activities. 4 Treatment with fibrates did not produce peroxisoma l proliferation in guinea-pigs, as measured by peroxisomal beta-oxidat ion activity and liver weight/body weight ratio. Nevertheless, fibrate s provoked a reduction in plasma cholesterol and triglycerides, at lea st in GFB- and BFB-treated animals. 5 Fatty acid elongation was signif icantly modified by GFB treatment in vivo. The remaining enzyme activi ties studied were only slightly changed by fibrate treatment. 6 Treatm ent with BFB and to a lesser extent with CFB, increased the relative p roportion of MUFA (palmitoleic and oleic acids) in microsomal phosphol ipids, whereas PUFA (mainly linoleic acid) decreased. GFB behaved diff erently, increasing palmitic and linoleic acids and decreasing stearic and oleic acids. The latter changes are attributable to an inhibition of elongation activity by GFB. 7 The changes observed after fibrate t reatment in both rats and guinea-pigs, as they are not directly relate d to peroxisome proliferation, could be more reliably extrapolated to man than those observed only in rats.