Insulin-stimulated degradation of apolipoprotein B100: roles of class II phosphatidylinositol-3-kinase and autophagy.
Insulin-stimulated degradation of apolipoprotein B100: roles of class II phosphatidylinositol-3-kinase and autophagy.
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DOI：
10.1371/journal.pone.0057590
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fisher EA
中科院分区：
文献类型：
--
作者：
Andreo U;Guo L;Chirieac DV;Tuyama AC;Montenont E;Brodsky JL;Fisher EA
在人类和动物模型中，血浆胰岛素水平急剧升高（通常在餐后）会导致肝脏极低密度脂蛋白（VLDL）分泌的短暂抑制。 VLDL 分泌减少的一种机制是载脂蛋白 B100 (apoB100) 的降解增强，这是 VLDL 形成所必需的。与在内质网 (ER) 中发生的新生 apoB100 降解不同，胰岛素刺激的 apoB100 降解发生在 ER 后，并被泛磷脂酰肌醇 (PI)3 激酶抑制剂抑制。然而，尚不清楚胰岛素刺激的 apoB100 降解需要三类 PI3 激酶中的哪一类，以及这种反应背后的蛋白水解机制。 III 类 PI3 激酶不被胰岛素激活，但其他两类可以。通过对肝脏中主要的 II 类亚型使用 I 类特异性抑制剂和 siRNA，我们现在证明 II 类 PI3 激酶是原代小鼠肝细胞中胰岛素刺激的 apoB100 降解所必需的。因为胰岛素刺激的过程类似于自噬介导的 apoB100 内质网后蛋白水解的其他例子，我们假设胰岛素在自噬缺陷的小鼠原代肝细胞中的作用会减弱。事实上，在两种自噬缺陷型肝细胞中，apoB100 对胰岛素的降解反应明显受损。总之，我们的数据表明，肝脏中胰岛素刺激的 apoB100 降解需要 II 类 PI3 激酶活性和自噬。
Both in humans and animal models, an acute increase in plasma insulin levels, typically following meals, leads to transient depression of hepatic secretion of very low density lipoproteins (VLDL). One contributing mechanism for the decrease in VLDL secretion is enhanced degradation of apolipoprotein B100 (apoB100), which is required for VLDL formation. Unlike the degradation of nascent apoB100, which occurs in the endoplasmic reticulum (ER), insulin-stimulated apoB100 degradation occurs post-ER and is inhibited by pan-phosphatidylinositol (PI)3-kinase inhibitors. It is unclear, however, which of the three classes of PI3-kinases is required for insulin-stimulated apoB100 degradation, as well as the proteolytic machinery underlying this response. Class III PI3-kinase is not activated by insulin, but the other two classes are. By using a class I-specific inhibitor and siRNA to the major class II isoform in liver, we now show that it is class II PI3-kinase that is required for insulin-stimulated apoB100 degradation in primary mouse hepatocytes. Because the insulin-stimulated process resembles other examples of apoB100 post-ER proteolysis mediated by autophagy, we hypothesized that the effects of insulin in autophagy-deficient mouse primary hepatocytes would be attenuated. Indeed, apoB100 degradation in response to insulin was significantly impaired in two types of autophagy-deficient hepatocytes. Together, our data demonstrate that insulin-stimulated apoB100 degradation in the liver requires both class II PI3-kinase activity and autophagy.
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DOI：
10.1152/ajpendo.2000.279.5.e1003
发表时间：
2000-11-01
影响因子：
5.1
作者：
Chirieac, DV;Chirieac, LR;Sparks, JD
通讯作者：
Sparks, JD
影响因子：
4.8
作者：
Fisher, EA;Pan, M;Williams, KJ
通讯作者：
Williams, KJ
影响因子：
56.9
作者：
CHEN, SH;HABIB, G;CHAN, L
通讯作者：
CHAN, L
影响因子：
7.7
作者：
LEWIS, GF;UFFELMAN, KD;STEINER, G
通讯作者：
STEINER, G
影响因子：
64.5
作者：
Knight, Zachary A.;Gonzalez, Beatriz;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.