Increased formation of polyunsaturated fatty acids and the physiological significance

给啮齿动物服用一种降血脂药物——纤维酸，已知会引起过氧化物酶体的增殖和肝肿大。该药物在较小程度上刺激线粒体和内质网的增殖。虽然肝脏对药物的这些反应被认为需要大量的磷脂作为生物膜的成分，但关于肝细胞为生物膜的形成增加磷脂供应的机制的信息很少。本文对其机理进行了研究，得到了以下结果：(1)纤维酸诱导肝脏脂肪酸去饱和酶，使油酸和花生四烯酸的生成增加。(2)经该药治疗后，肝脏磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）浓度升高。肝内PC浓度的升高是通过提高PC的新生合成活性引起的，而通过降低代谢速率而不是通过增加新生合成活性来增加PE浓度。(3)形成的油酸主要用于PC的棕榈酰基油酰基的形成，而形成的花生四烯酸优先用于PE的棕榈酰基花生四烯酰基和硬脂酰花生四烯酰基的形成。(4)纤维酸降低了PC中硬脂酰-花生四烯酰基物种的比例，导致血清花生四烯酸水平降低。由于肾脏很少产生花生四烯酸，血清花生四烯酸的减少降低了肾PC中花生四烯酸的比例，从而降低了前列腺素E_2的形成。这些结果表明，肝细胞通过诱导酶和减少周转来增加磷脂的供应，以维持具有适当流动性的生物源膜的增殖，肝脏的变化导致肾脏前列腺素的减少。少

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