RELATIONSHIP BETWEEN PLASMA-LIPIDS AND PALMITOYL-COA HYDROLASE AND SYNTHETASE ACTIVITIES WITH PEROXISOMAL PROLIFERATION IN RATS TREATED WITH FIBRATES

1 The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-CoA hydrol ase and synthetase activities, as well as the correlations with the pe roxisomal proliferation phenomenon have been studied in male Sprague-D awley rats. 2 The administration of the three drugs caused a significa nt reduction in body weight gain, accompanied with a paradoxical incre ase in food intake in groups treated with BFB and GFB. 3 Drug treatmen t produced gross hepatomegaly and increase in peroxisomal beta-oxidati on, and these parameters were strongly correlated. The order of potenc y was BFB>CFB greater than or equal to GFB. 4 Both plasma cholesterol (BFB approximate to CFB>GFB) and triglyceride (BFB approximate to GFB> CFB) levels were reduced in treated animals. There was an inverse corr elation between these parameters and peroxisomal beta-oxidation, altho ugh the peroxisomal proliferation seemed to explain only a small part of the hypolipidemic effect observed. 5 Cytosolic and microsomal (but not mitochondrial) palmitoyl-CoA hydrolase activities were increased b y the three drugs (BFB>CFB>GFB), probably by inducing the hydrolase I isoform, which is insensitive to inhibition by fibrates in vitro. The increased hydrolase activities were directly and strongly correlated w ith peroxisomal beta-oxidation. 6 Palmitoyl-CoA synthetase activity wa s also increased by the treatment with fibrates (BFB>CFB >GFB), probab ly as a consequence of the enhancement of hydrolase activities. 7 Some of the effects of fibrate treatment can be explained, at least in par t, in terms of peroxisomal induction and caution should be exercised i n the extrapolation of these results to species, such as man, that are insensitive to peroxisomal proliferation.