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Diabetologia:胰腺β细胞内脂肪回收系统决定胰岛素分泌量

来源:生物谷 2013-10-29 23:30

2013年10月29日讯 /生物谷BIOON/--胰腺是一个大的器官,围绕我们的肠道,当我们吃东西时,胰腺产生身体需要的确切数额的胰岛素。但当我们开始发展罹患糖尿病时,胰岛素生产减慢。

近日,悉尼科学家们描述了胰腺β细胞内的脂肪回收系统如何确定β细胞分泌胰岛素的量,或将揭示未来糖尿病的治疗靶标。

β细胞的一个小的内部结构--溶酶体,就像细胞内的一个“回收机组”,分解多余的脂肪和蛋白质,被分解的脂肪和蛋白质可以被重新利用。

悉尼加尔文医学研究所博士生Gemma Pearson和教授Trevor Biden表明,当他们抑制溶酶体分解脂肪后,β细胞分泌更多的胰岛素。他们的研究结果发表在Diabetologia杂志上。

虽然新研究发现仅是一个非常早期阶段的细胞生物学故事,但它鼓励科学界通过研究脂肪来对糖尿病进行治疗。

通过检查β细胞血脂谱,Gemma Pearson博士说:有许多不同的方法可以使用β细胞内脂肪,所以如果你阻止脂肪被回收,你就可以迫使脂肪以不同的方式被利用。

当你从溶酶体中转移脂肪,将它们存储在细胞其他部位,这些脂肪就参加各种信号通路,这些通路之一在胰岛素分泌过程中明显活性增加。脂肪分子可以结合蛋白质并激活它们,造成下游的一系列事件发生。(生物谷Bioon.com)

Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells

Hiroyasu Yamamoto, Evan G. Williams, Laurent Mouchiroud, Carles Cantó, Weiwei Fan, Michael Downes, Christophe Héligon, Grant D. Barish, Béatrice Desvergne, Ronald M. Evans et al.

Aims/hypothesis
Lipolytic breakdown of endogenous lipid pools in pancreatic beta cells contributes to glucose-stimulated insulin secretion (GSIS) and is thought to be mediated by acute activation of neutral lipases in the amplification pathway. Recently it has been shown in other cell types that endogenous lipid can be metabolised by autophagy, and this lipophagy is catalysed by lysosomal acid lipase (LAL). This study aimed to elucidate a role for LAL and lipophagy in pancreatic beta cells.

Methods
We employed pharmacological and/or genetic inhibition of autophagy and LAL in MIN6 cells and primary islets. Insulin secretion following inhibition was measured using RIA. Lipid accumulation was assessed by MS and confocal microscopy (to visualise lipid droplets) and autophagic flux was analysed by western blot.

Results
Insulin secretion was increased following chronic (≥8 h) inhibition of LAL. This was more pronounced with glucose than with non-nutrient stimuli and was accompanied by augmentation of neutral lipid species. Similarly, following inhibition of autophagy in MIN6 cells, the number of lipid droplets was increased and GSIS was potentiated. Inhibition of LAL or autophagy in primary islets also increased insulin secretion. This augmentation of GSIS following LAL or autophagy inhibition was dependent on the acute activation of neutral lipases.

Conclusions/interpretation
Our data suggest that lysosomal lipid degradation, using LAL and potentially lipophagy, contributes to neutral lipid turnover in beta cells. It also serves as a constitutive negative regulator of GSIS by depletion of substrate for the non-lysosomal neutral lipases that are activated acutely by glucose.

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