Cholesterol Sulfate Exerts Protective Effect on Pancreatic β-Cells by Regulating β-Cell Mass and Insulin Secretion.
Cholesterol Sulfate Exerts Protective Effect on Pancreatic β-Cells by Regulating β-Cell Mass and Insulin Secretion.
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硫酸胆固醇通过调节β细胞质量和胰岛素分泌对胰腺β细胞发挥保护作用
DOI：
10.3389/fphar.2022.840406
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发表时间：
2022
影响因子：
5.6
通讯作者：
Su Z
中科院分区：
文献类型：
--
作者：
Zhang X;Deng D;Cui D;Liu Y;He S;Zhang H;Xie Y;Yu X;Yang S;Chen Y;Su Z
理由：硫酸胆固醇（Cholesterol sulfate，CS）是人体血浆中含量最丰富的一种甾醇硫酸盐，在调节代谢和炎症反应中起重要作用，而炎症反应又是胰岛素抵抗、β细胞功能障碍和糖尿病的发病机制之一。然而，CS在β细胞中的作用及其对糖尿病发展的影响仍然未知。在这里，我们确定了CS在胰腺β细胞稳态中的生理功能。 材料与方法：通过LC-MS/MS测定链脲佐菌素（STZ）或高脂饮食诱导的糖尿病小鼠和1型或2型糖尿病患者的血液CS水平。在离体小鼠胰岛和β细胞系INS-1中体外研究CS对β细胞质量和胰岛素分泌的影响，并在STZ诱导的糖尿病小鼠中体内研究CS对β细胞质量和胰岛素分泌的影响。通过细胞活力测定、EdU掺入分析、流式细胞术、细胞内Ca 2+内流分析、线粒体膜电位和细胞内ROS测定以及代谢检测试剂盒等方法探讨CS的分子机制。 结果：糖尿病状态下，小鼠和人血浆CS水平显著升高。CS在低剂量STZ诱导的小鼠模型中减轻糖尿病。在机制上，CS促进β-细胞增殖并保护β-细胞在应激条件下免于凋亡，这反过来又保护β-细胞质量。此外，CS支持葡萄糖转运蛋白-2（GLUT 2）表达和线粒体完整性，从而导致活性氧（ROS）生成减少和ATP生成增加，从而使胰岛中的胰岛素分泌机制充分发挥作用。 结论：这项研究揭示了CS在整合β细胞存活和细胞功能方面的新的双重作用，表明CS可能提供一种生理方法来保护β细胞并防止糖尿病的发展。
Rational: Cholesterol sulfate (CS) is the most abundant known sterol sulfate in human plasma, and it plays a significant role in the control of metabolism and inflammatory response, which contribute to the pathogenesis of insulin resistance, β-cell dysfunction and the resultant development of diabetes. However, the role of CS in β-cells and its effect on the development of diabetes remain unknown. Here, we determined the physiological function of CS in pancreatic β-cell homeostasis. Materials and Methods: Blood CS levels in streptozotocin (STZ)- or high-fat diet-induced diabetic mice and patients with type 1 or 2 diabetes were determined by LC-MS/MS. The impact of CS on β-cell mass and insulin secretion was investigated in vitro in isolated mouse islets and the β-cell line INS-1 and in vivo in STZ-induced diabetic mice. The molecular mechanism of CS was explored by viability assay, EdU incorporation analysis, flow cytometry, intracellular Ca2+ influx analysis, mitochondrial membrane potential and cellular ROS assays, and metabolism assay kits. Results: Plasma CS levels in mice and humans were significantly elevated under diabetic conditions. CS attenuated diabetes in a low-dose STZ-induced mouse model. Mechanistically, CS promoted β-cell proliferation and protected β-cells against apoptosis under stressful conditions, which in turn preserved β-cell mass. In addition, CS supported glucose transporter-2 (GLUT2) expression and mitochondrial integrity, which then resulted in a less reactive oxygen species (ROS) generation and an increase in ATP production, thereby enabling insulin secretion machinery in the islets to function adequately. Conclusion: This study revealed a novel dual role of CS in integrating β-cell survival and cell function, suggesting that CS might offer a physiologic approach to preserve β-cells and protect against the development of diabetes mellitus.
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影响因子：
16.6
作者：
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