Intracellular free fatty acid upholds β-cell glucose competence: The role of peroxisome proliferator-activated receptor δ and mitochondrial metabolism.
Intracellular free fatty acid upholds β-cell glucose competence: The role of peroxisome proliferator-activated receptor δ and mitochondrial metabolism.
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DOI：
10.1111/jdi.12257
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发表时间：
2015-03
影响因子：
3.2
通讯作者：
Aizawa T
中科院分区：
文献类型：
--
作者：
Takei M;Komatsu M;Aizawa T
胞外葡萄糖的升高导致b颗粒和质膜的融合，这是由于膜下钙离子浓度增加的结果。三磷酸腺苷(ATP)/二磷酸腺苷(ADP)比值的升高是这一过程的关键，因为它导致ATP敏感的K+(KATP)通道关闭，膜去极化，电压依赖性钙通道开放，最终钙离子从细胞外部内流。此后不久，随着可释放的b颗粒池的补充，葡萄糖刺激的胰岛素分泌(GSIS)增加。虽然这种增强的分子基础还没有完全确定，但游离脂肪酸(FFA)被认为在这一过程中起着不可或缺的作用。游离脂肪酸的量在微摩尔范围内，因此太少，不能产生经典的代谢偶联因子(S)，如用于胰岛素胞吐的三磷酸腺苷，当与刺激浓度的葡萄糖1一起加入孵育时，会增强GSI。此外，在没有葡萄糖刺激浓度的情况下，将b细胞预先暴露在类似低浓度的FFA中，使细胞在任何刺激下随后引发的胰岛素释放(IR)比未经FFA1处理的b细胞增强。B细胞持续暴露于高浓度葡萄糖会导致三羧酸(TCA)循环中柠檬酸的无性输出，升高胞浆丙二酰辅酶A，从而抑制肉碱棕榈酰转移酶1，导致FFA进入线粒体2的减少。随后胞内游离脂肪酸的积累可能通过胞吐作用中的关键蛋白(S)的脂肪酰化来增加胰岛素的分泌。相反，增加细胞脂肪酰辅酶A(FA-CoA)也可以通过甘油脂/FFA周期2增强IR。短发夹状核糖核酸抑制GSIS4基因敲除b细胞中的去核苷/脂肪甘油三酯脂肪酶(ATGL)所有这些数据表明，b细胞细胞内FFA的急性升高和降低分别增强和抑制了GSIS。然而，FFA调节胰岛素分泌的下游效应器仍然难以捉摸，特别是在b细胞特异性降低细胞内FFA的情况下。
Elevation of extracellular glucose causes fusion of the b granules and the plasma membrane as a result of increased submembrane Ca2+ concentration. A raised adenosine triphosphate (ATP)-to-adenosine diphosphate (ADP) ratio is pivotal to this process, as it causes closure of the ATP-sensitive K+(KATP) channel, membrane depolarization, opening of voltagedependent calcium channels and finally Ca2+ influx from the cell exterior. Soon thereafter, glucose-stimulated insulin secretion (GSIS) is augmented as the releasable pool of b granules is replenished. Although the molecular basis of this augmentation has not been fully defined, free fatty acid (FFA) has been strongly implicated as having an indispensable role in this process. Quantities of FFA in the micromolar range, and therefore too minute to generate classic metabolic coupling factor (s), such as ATP for insulin exocytosis, enhance GSIS when added to the incubation in conjunction with a stimulatory concentration of glucose1. Furthermore, pre-exposure of b-cells to a similarly low concentration of FFA in the absence of a stimulatory concentration of glucose primes the cells so that the insulin release (IR) subsequently provoked by any stimulation is enhanced compared with that in b-cells not treated with FFA1. Continued exposure of b-cells to a high concentration of glucose causes an anaplerotic output of citrate from the tricarboxylic acid (TCA) cycle, elevating cytosolic malonyl-CoA, which causes suppression of carnitine palmitoyltransferase 1 leading to decreased FFA entry to mitochondria2. The subsequent accumulation of cytosolic FFA might increase insulin secretion through fatty acylation of key protein (s) involved in exocytosis3. In contrast, increased cellular fatty acyl-CoA (FA-CoA) could also enhance IR through the glycerolipid/FFA cycle2. Knockdown of desnutrin/adipose triglyceride lipase (ATGL) in b-cells by short hairpin ribonucleic acid suppressed GSIS4. All of these data show that acute elevation and lowering of cellular FFA in b-cells, respectively, enhanced and suppressed GSIS. However, the downstream effector or effectors of FFA regulation of insulin secretion have remained elusive, especially under the conditions of sustained b-cell specific lowering of intracellular FFA.
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影响因子：
7.7
作者：
Komatsu, M;Yajima, H;Aizawa, T
通讯作者：
Aizawa, T
影响因子：
4.8
作者：
Yamada, S;Komatsu, M;Kojima, I
通讯作者：
Kojima, I
影响因子：
29
作者：
Tang T;Abbott MJ;Ahmadian M;Lopes AB;Wang Y;Sul HS
通讯作者：
Sul HS
影响因子：
4.8
作者：
Peyot, Marie-Line;Guay, Claudiane;Prentki, Marc
通讯作者：
Prentki, Marc
影响因子：
4
作者：
ISHIHARA, F;AIZAWA, T;HASHIZUME, K
通讯作者：
HASHIZUME, K