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Effect of different hypolipemic agents on rat liver peroxisomal and mitochondrial functions and biogenesis
M Cherkaoui Malki1, L Assaka, C Pacot
1Laboratoire de Biologie Moléculaire et Cellulaire, Faculté des Sciences Mirande, Université de Bourgogne, Dijon, France.
Abstract:
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).
Insights
Fibrate analogues, including the herbicide 2,4-D, strongly promote peroxisome proliferation in rats. While mitochondria are less affected, ciprofibrate shows differential regulatory effects on lipid metabolism enzymes.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Fibrate analogues are known hypolipidemic agents.
- Their effects on liver organelle biogenesis require detailed investigation.
Purpose of the Study:
- To investigate the in vivo effects of four fibrate analogues on liver mitochondrial and peroxisomal protein biogenesis in rats.
- To compare the distinct impacts of clofibrate, ciprofibrate, clobuzarit, and 2,4-D on cellular organelles.
Main Methods:
- In vivo rat treatment with fibrates (100 ppm for 26 weeks).
- Analysis included somatic index, histochemistry, electron microscopy, enzyme activity assays, electrophoresis, immunolabeling, and mRNA hybridization.
- Specific focus on mitochondrial and peroxisomal proteins and their corresponding mRNA levels.
Main Results:
- Fibrates, particularly ciprofibrate, are potent peroxisomal proliferators; mitochondria are less affected.
- 2,4-D significantly altered the mitochondrial polypeptide pattern.
- Catalase mRNA showed a slight increase, while acyl-CoA oxidase and R-3-hydroxybutyrate dehydrogenase (BDH) mRNA levels were enhanced by ciprofibrate.
Conclusions:
- Fibrates differentially affect liver organelle biogenesis, with varying impacts on mitochondria and peroxisomes.
- Ciprofibrate exhibits dual regulatory effects on BDH, influencing both its mRNA levels and enzyme activity, suggesting complex lipid metabolism regulation.