Diabetes Research Center, Brussels Free University-VUB, and JDRF Center for Beta Cell Therapy in Diabetes, Brussels, Belgium.
PLoS One. 2009 Sep 29;4(9):e7266. doi: 10.1371/journal.pone.0007266.
Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/-) and LXRalphabeta(-/-)), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.
慢性高水平的脂肪酸（FA）可导致体外β细胞死亡。β细胞对 FA 毒性的个体易感性不同。先前的研究表明，在增加甘油三酯形成或线粒体和过氧化物酶体 FA 氧化的条件下，大鼠β细胞对 FA 毒性的抵抗力更好，可能会降低细胞质中有毒 FA 部分的水平。我们现在表明，硬脂酰辅酶 A 去饱和酶（SCD）通过将饱和 FA 转移到单不饱和 FA 并将其掺入脂质中来参与这种细胞保护机制。在纯化的β细胞中，SCD 表达受 LXR 和 PPARalpha 激动剂诱导，发现这些激动剂可保护大鼠、小鼠和人β细胞免受棕榈酸盐毒性。当它们的 SCD 被抑制或沉默时，激动剂诱导的保护也被抑制。在从不同啮齿动物模型分离的β细胞制剂中，也发现了β细胞-SCD 表达与对棕榈酸盐的易感性之间存在相关性。在 LXR 缺失（LXRbeta(-/-) 和 LXRalphabeta(-/-)）的小鼠中，β细胞的 SCD 表达减少，对棕榈酸盐的敏感性增加，LXR 或 PPARalpha 激动剂无法逆转这种情况。在 Zucker 肥胖大鼠和用 LXR 激动剂 TO1317 治疗的大鼠中，β细胞显示 SCD 表达增加，棕榈酸盐毒性降低。在正常大鼠β细胞群体中，对葡萄糖代谢反应性较低的亚群 SCD1 表达较低，对棕榈酸盐毒性的敏感性较高。这些数据表明，硬脂酰辅酶 A 去饱和酶可降低β细胞对饱和脂肪酸的敏感性，LXR 和 PPARalpha 激动剂刺激后，它有利于饱和脂肪酸的去饱和及其随后掺入中性脂质。
