Intestinal assembly and secretion of highly dense/lipid-poor apolipoprotein B48-containing lipoprotein particles in the fasting state: Evidence for induction by insulin resistance and exogenous fatty acids
Intestinal assembly and secretion of highly dense/lipid-poor apolipoprotein B48-containing lipoprotein particles in the fasting state: Evidence for induction by insulin resistance and exogenous fatty acids
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DOI：
10.1016/j.metabol.2004.12.014
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发表时间：
2005-05-01
影响因子：
9.8
通讯作者：
Adeli, K
中科院分区：
文献类型：
--
作者：
Guo, QS;Avramoglu, RK;Adeli, K
新出现的证据表明，肠源性载脂蛋白 (apo) B48 的脂蛋白颗粒的过量产生可能是胰岛素抵抗状态下空腹和餐后血脂异常的重要原因。调节含 apoB48 脂蛋白的组装和分泌的机制尚未完全了解，特别是在糖尿病/胰岛素抵抗肠道中。在本研究中，我们研究了原代仓鼠肠上皮细胞中组装的 apoB48 脂蛋白的密度分布。在从正常或胰岛素抵抗果糖喂养的仓鼠中分离的肠上皮细胞以及用外源油酸处理的肠上皮细胞中检查了细胞内和分泌的 apoB48 颗粒。分别通过蔗糖和 KBr 梯度的不连续和连续超速离心来分析微粒体腔内容物和培养基。在禁食状态下，ApoB48 主要分泌在 VLDL、LDL 和密度较高的 HDL 大小的颗粒上。在脉冲追踪标记实验中，新生的含有 apoB48 的颗粒最初以 HDL 大小的颗粒形式积累在微粒体腔中，随后形成 apoB48-VLDL 颗粒，仅观察到微量的乳糜微粒。用 720 μmol/L 油酸处理，增加了微粒体 apoB48 HDL 的合成，并诱导了向更轻、更有浮力的颗粒的显着转变。在果糖喂养的仓鼠肠上皮细胞的微粒体腔中也观察到含有 apoB48 的脂蛋白组装显着增强，这表明在胰岛素抵抗状态下促进了致密肠脂蛋白颗粒的组装和分泌。总体而言，这些观察结果表明，大部分含有 apoB48 的脂蛋白颗粒被组装并分泌为高密度、HDL 大小的颗粒。这些小而致密且可能导致动脉粥样硬化的 apoB48 颗粒的产生可以通过增加游离脂肪酸通量以及胰岛素抵抗糖尿病来刺激。 (c) 2005 Elsevier Inc. 保留所有权利。
Emerging evidence suggests that overproduction of intestinally derived apolipoprotein (apo) B48-containing lipoprotein particles may be an important contributor to both fasting and postprandial dyslipidemia in insulin-resistant states. Mechanisms regulating the assembly and secretion of apoB48-containing lipoproteins are not fully understood particularly in the diabetic/insulin-resistant intestine. In the present study, we have investigated the density profile of apoB48 lipoproteins assembled in primary hamster enterocytes. Both intracellular and secreted apoB48 particles were examined in intestinal enterocytes isolated from normal or insulin-resistant fructose-fed hamsters, as well as in enterocytes treated with exogenous oleic acid. Microsomal luminal contents and culture media were analyzed by discontinuous and sequential ultracentrifugation on sucrose and KBr gradients, respectively. ApoB48 was mostly secreted on VLDL-, LDL-, and denser HDL-sized particles in the fasting state. In pulse-chase labeling experiments, nascent apoB48-containing particles initially accumulated in the microsomal lumen as HDL-sized particles, with subsequent formation of apoB48-VLDL particles, with only a minute amount of chylomicrons observed. Treatment with 720 mu mol/L of oleic acid, increased microsomal apoB48 HDL synthesis, and induced a marked shift toward lighter more buoyant particles. A marked enhancement in assembly of apoB48-containing lipoproteins was also observed in the microsomal lumen of fructose-fed hamster enterocytes, suggesting facilitated assembly and secretion of dense intestinal lipoprotein particles in insulin-resistant states. Overall, these observations suggest that a major proportion of apoB48-containing lipoprotein particles is assembled and secreted as highly dense, HDL-sized particles. The production of these small, dense, and potentially atherogenic apoB48 particles can be stimulated by increased free fatty acid flux as well as in insulin-resistant diabetes. (c) 2005 Elsevier Inc. All rights reserved.