Effect of different hypolipemic agents on rat liver peroxisomal and mitochondrial functions and biogenesis.

The effect of four fibrate analogues (i.e. clofibrate, ciprofibrate, clobuzarit and 2,4-dichlorophenoxyacetic acid (2,4-D), an active herbicide molecule) were tested on the biogenesis of liver mitochondrial and peroxisomal proteins by rat in vivo treatment at 100 ppm for 26 weeks. The evaluations were done at different levels: somatic index, histochemistry electron microscopy, enzymatic activities on purified peroxisomes and mitochondria, polypeptides electrophoresis and immunolabeling, and finally mRNA hybridization with specific DNA probes. This work shows that the tested hypolipemic agents are strong peroxisomal proliferators especially ciprofibrate, while mitochondria are weakly affected. However, the four fibrates gave different effects, especially 2,4-D which modifies mitochondrial polypeptide pattern. Post-transcriptional study of mRNAs level shows a slight increase in catalase mRNA despite the potential of hypolipemic agents. The peroxisomal acyl-CoA oxidase mRNA content is enhanced with ciprofibrate treatment as well as mitochondrial R-3-hydroxybutyrate dehydrogenase (BDH) mRNA level. Finally, the dual action of ciprofibrate on content and on enzymatic activity of BDH (a lipid metabolism related enzyme) reveals that such a molecule may have differential regulatory effects (positive on gene transcription or mRNA stability and negative on catalytic enzyme activity).