Relationship between morphological changes and lipid-lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man

Abstract

In order to elucidate the effect of long-term treatment with CPIB on the ultrastructure of the human liver, we measured the numerical and volume density of mitochondria and peroxisomes per cm 3 of liver tissue by morphometric procedures before and during prolonged intake of the drug in 16 patients with primary hypertriglyceridemia. We correlated the number and volume of mitochondria and peroxisomes to serum triglyceride and cholesterol concentrations and changes in order to obtain information on the interrelationship of organelle changes and lipid-lowering action. CPIB treatment resulted in significant increases in the numerical density of mitochondria and peroxisomes (38% and 50%, respectively, P < 0.01). The volume density for mitochondria and peroxisomes increased by 34% ( P < 0.01) and 23% (NS) respectively. After a marked proliferation of both organelles during the first months no further significant increase was observed. The fall in triglyceride and cholesterol levels during the initial period was followed by constant concentrations. A significant correlation between numerical and volume density of mitochondria and peroxisomes occurred during treatment indicating a well-balanced adapted process. There was a significant reverse correlation between the increase in volume density of mitochondria and the decrease in triglyceride levels, whereas no relation between the proliferation of peroxisomes and hypolipidemic action existed. In our study long-term treatment with CPIB had no toxic or carcinogenic effects on the human liver. Contrary to the fine structural changes in the rodents, the proliferation of peroxisomes is less pronounced and proportional to the increase in mitochondria. The correlation between mitochondrial proliferation and the triglyceride-lowering effect supports the hypothesis that CPIB reduces hepatic triglyceride synthesis by an increase in mitochondria associated with elevated activity of glycerol-3-phosphate dehydrogenase.