Perfluorooctanoic acid, a peroxisome-proliferating hypolipidemic agent, dissociates apolipoprotein B48 from lipoprotein particles and decreases secretion of very low density lipoproteins by cultured rat hepatocytes
Perfluorooctanoic acid, a peroxisome-proliferating hypolipidemic agent, dissociates apolipoprotein B48 from lipoprotein particles and decreases secretion of very low density lipoproteins by cultured rat hepatocytes
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DOI：
10.1016/s1388-1981(99)00024-4
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发表时间：
1999-03-25
影响因子：
4.8
通讯作者：
Takahashi, A
中科院分区：
文献类型：
--
作者：
Okochi, E;Nishimaki-Mogami, T;Takahashi, A
各种过氧化物体增殖物均可引起降血脂作用。通过过氧化物酶体增殖物激活受体(PPAR)对基因转录的调控通常是导致这种效应的原因。此外，我们还发现了一种PPAR不依赖的机制，在该机制中，已知的过氧化物酶体增殖物贝特类通过磷脂酰乙醇胺(PE)的甲基化抑制磷脂酰胆碱的合成，减少肝脏极低密度脂蛋白(VLDL)的分泌(T.Nishimaki-Mogami等人，Biochim)。生物群落。学报1304(1996)21-31)。在这项研究中，我们展示了一种新的机制，全氟辛酸(PFOA)，一个有效的过氧化物酶增殖剂和PE甲基化的抑制剂，发挥其降血脂作用。加入全氟辛酸(100 MU M)可使培养的大鼠肝细胞甘油三酯的分泌量迅速下降，且与细胞PE甲基化活性无关。对分泌到培养液中的apoB密度的分析表明，PFOA降低了极低密度脂蛋白中的apoB48，但增加了底端d>；1.21组分中的apoB48。这种脂类贫乏的apoB48也是通过与PFOA从对照细胞中获得的孵育液产生的，表明PFOA具有从脂蛋白颗粒中解离apoB48的能力。在实验前将细胞暴露于全氟辛酸2小时足以产生脂质贫乏的载脂蛋白B48，表明全氟辛酸在细胞内发挥作用。综上所述，这些数据表明，全氟辛酸与载脂蛋白B48的强烈相互作用干扰了载脂蛋白B48在细胞内极低密度脂蛋白组装过程中与脂质的关联，从而抑制了极低密度脂蛋白的分泌。本研究表明，不同种类的过氧化物酶体增殖物的降血脂作用机制不同。(C)1999 Elsevier Science B.V.保留所有权利。
The hypolipidemic effect is evoked by various peroxisome proliferators. Modulation of gene transcription via peroxisome proliferator-activated receptor (PPAR) is generally responsible for this effect. In addition, we have found a PPAR-independent mechanism in which fibrates, known peroxisome proliferators, decrease hepatic secretion of very low density lipoproteins (VLDL) through inhibition of phosphatidylcholine synthesis via methylation of phosphatidylethanolamine (PE) (T. Nishimaki-Mogami et al., Biochim. Biophys. Acta 1304 (1996) 21-31). In the present study, we show a novel mechanism by which perfluorooctanoic acid (PFOA), a potent peroxisome proliferator and inhibitor of PE methylation, exerts its hypolipidemic effect. PFOA (100 mu M) added to the medium rapidly decreased the secretion of triglyceride by cultured rat hepatocytes, which was independent of the activity of cellular PE methylation. Analysis of the density of apoB secreted into the medium showed that PFOA decreased apoB48 in VLDL, but increased apoB48 in the bottom d> 1.21 fraction. This lipid-poor apoB48 was also generated by incubating medium that had been harvested from control cells with PFOA, indicating that PFOA has the ability to dissociate apoB48 from lipoprotein particles. Exposure of cells to PFOA for 2 h prior to the experiment was sufficient to generate lipid-poor apoB48, indicating that PFOA exerted its effect intracellularly. Taken together, the data suggest that a strong interaction of PFOA with apoB48 disturbs the association of apoB48 with lipids in the process of intracellular VLDL assembly, thereby inhibiting VLDL secretion. This study shows that the mechanisms of hypolipidemic effect caused by various classes of peroxisome proliferators are diverse. (C) 1999 Elsevier Science B.V. All rights reserved.