Increased formation of polyunsaturated fatty acids and the physiological significance

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Administration of clofibric acid, a hypolipidemic drug, to rodents is known to cause proliferation of peroxisomes and hepatomegaly. The drug stimulates, to a lesser extent, proliferation of mitochondria and endolpasmic reticulum as well. Although these responses of liver to the drug are supposed to require a large amounts of phospholipids as the constituents of biogenic membranes, little information is available about the mechanism by which hepatocytes increase the supply of phospholipids for the biogenesis of membranes. The present work investigated the mechanism and obtained the following results. (1) Clofibric acid induced hepatic fatty-acid desaturases so that the formations of oleic acid and arachidonic acid were increased. (2) Upon the treatment with this drug, hepatic concentrations of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased. The increase in hepatic concentration of PC was caused by enhancing the activity of synthesis de novo of PC, and the conc … More entration of PE was increased by reducing the rate of turnover, but not by increasing the activity of synthesis de novo. (3) Oleic acid formed was mainly channeled to formation of palmitoyl-oleoyl species of PC, and arachidonic acid formed was preferentially utilized for formation of palmitoyl-arachidonoyl and stearoyl-arachidonoyl species of PE. (4) The administration of clofibric acid decreased a proportion of stearoyl- arachidonoyl species in PC, and the decrease caused the reduction in the level of serum arachidonic acid. Since kidney little produced arachidonic acid, the reduction in serum arachidonic acid decreased the proportion of arachidonic acid in renal PC so that formation of prostaglandin E_2 was lowered. These results suggest that hepatocytes increase the supply of phospholipids by inducing enzymes and by reducing turnover to maintain proliferating biogenic membranes with appropriate fluidity and that the changes induced in liver resulted in the reduction of prostaglandin in kidney. Less