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阿托伐他汀对HepG2细胞内载脂蛋白B稳定性及分泌的影响。

Effects of atorvastatin on the intracellular stability and secretion of apolipoprotein B in HepG2 cells.

作者信息

Mohammadi A, Macri J, Newton R, Romain T, Dulay D, Adeli K

机构信息

Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada.

出版信息

Arterioscler Thromb Vasc Biol. 1998 May;18(5):783-93. doi: 10.1161/01.atv.18.5.783.

Abstract

We investigated the effects of atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the biogenesis of apolipoprotein B (apoB) in intact and permeabilized HepG2 cells. Intact cells were pretreated either with single or multiple doses of atorvastatin (0.1 to 20 micromol/L) for periods of 6 to 20 hours and pulsed with [35S]methionine. In some cases the cells were permeabilized with digitonin. Experiments were performed to investigate the effects of atorvastatin on (1) the rates of lipid synthesis and secretion, (2) the synthesis and accumulation of apoB, (3) the intracellular stability of apoB, (4) the amount of apoB-containing lipoprotein particles assembled in HepG2 microsomes, and (5) the secretion and accumulation of apoB into the culture medium. ApoB synthesis, degradation, and secretion were measured by pulse-chase experiments with [35S]methionine in both intact and permeabilized HepG2 cells. Lipid synthesis was assessed by pulse-labeling experiments with [3H]acetate or [3H]oleate bound to bovine serum albumin. Comparisons were made under basal conditions and in the presence of oleate (0.36 micromol/L). Atorvastatin acutely inhibited the synthesis of cholesterol and cholesterol ester but did not have a significant effect on triglyceride or phospholipid synthesis. Atorvastatin did not affect the uptake of [35S]methionine by the cells nor did it influence the synthesis of apoB or a control protein, albumin. However, atorvastatin reduced the secretion of apoB into the culture medium, apparently by enhancing the degradation of apoB in the cell under basal and induced conditions with oleate. The stability of apoB associated with the lipoprotein particles was also significantly lowered by atorvastatin. The stimulated degradation of apoB in atorvastatin-treated cells was sensitive to MG132, a proteasome inhibitor. The net effect of atorvastatin was a reduction in the number of apoB-containing lipoprotein particles of different sizes isolated from microsomes and a reduction in apoB secretion into the culture medium. The data suggest that atorvastatin may impair the translocation of apoB into the lumen of the endoplasmic reticulum, thus increasing the amount of apoB degraded intracellularly. It is hypothesized that atorvastatin alters these parameters primarily as a result of inhibiting cholesterol synthesis and limiting the availability of cholesterol and/or cholesterol ester for the normal assembly of apoB-containing lipoprotein particles.

摘要

我们研究了新型3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂阿托伐他汀对完整及通透的HepG2细胞中载脂蛋白B(apoB)生物合成的影响。完整细胞用单剂量或多剂量阿托伐他汀(0.1至20微摩尔/升)预处理6至20小时,然后用[35S]甲硫氨酸脉冲标记。在某些情况下,细胞用洋地黄皂苷通透处理。进行实验以研究阿托伐他汀对以下方面的影响:(1)脂质合成和分泌速率;(2)apoB的合成和积累;(3)apoB在细胞内的稳定性;(4)在HepG2微粒体中组装的含apoB脂蛋白颗粒的数量;(5)apoB分泌到培养基中及在培养基中的积累。在完整及通透的HepG2细胞中,通过用[35S]甲硫氨酸进行脉冲追踪实验来测量apoB的合成、降解和分泌。脂质合成通过用与牛血清白蛋白结合的[3H]乙酸盐或[3H]油酸进行脉冲标记实验来评估。在基础条件下以及在油酸(0.36微摩尔/升)存在的情况下进行比较。阿托伐他汀可急性抑制胆固醇和胆固醇酯的合成,但对甘油三酯或磷脂合成无显著影响。阿托伐他汀不影响细胞对[35S]甲硫氨酸的摄取,也不影响apoB或对照蛋白白蛋白的合成。然而,阿托伐他汀可减少apoB分泌到培养基中,这显然是通过在基础条件下以及在油酸诱导条件下增强细胞内apoB的降解来实现的。阿托伐他汀还显著降低了与脂蛋白颗粒相关的apoB的稳定性。在阿托伐他汀处理的细胞中,apoB受刺激的降解对蛋白酶体抑制剂MG132敏感。阿托伐他汀的净效应是减少了从微粒体中分离出的不同大小的含apoB脂蛋白颗粒数量,并减少了apoB分泌到培养基中。数据表明,阿托伐他汀可能损害apoB向内质网腔的转运,从而增加细胞内降解的apoB量。据推测,阿托伐他汀改变这些参数主要是由于抑制胆固醇合成并限制了用于正常组装含apoB脂蛋白颗粒的胆固醇和/或胆固醇酯的可利用性。

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