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Fenofibrate

内分泌

关键词内分泌 治疗药物 降血脂类药物

词汇介绍

拓展阅读

解析

Fenofibrate

       n. 非诺贝特

       Objective To discuss the value of simvastatin plus fenofibrate for the treatment of mixed hyperlipemia. 目的探讨辛伐他汀联合非诺贝特治疗混合性高脂血症的价值。

概述

非诺贝特与低脂饮食,运动,有时与其他药物一起使用,以减少血液中胆固醇和甘油三酯等脂肪物质的含量,并增加HDL的含量,降低心脏病的风险。尽管非诺贝特降低了血液中脂肪物质的含量,但尚未证实可降低心脏病发作或中风的风险。非诺贝特属于一类叫做抗血脂药的药物。适应症非诺贝特与适当的饮食一起使用,以帮助降低“坏”胆固醇和脂肪(如低密度脂蛋白,甘油三酯),并提高血液中的“好”胆固醇(HDL)。它的作用是增加分解血液中脂肪的天然物质(酶)。非诺贝特属于一组被称为“贝特类”的药物,降低甘油三酯水平高的人群中的

Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice复制标题

非诺贝特增加NOD小鼠的超长链鞘脂类并改善血糖稳态

发表时间:2019-08-13

影响因子:7.1

作者: Laurits J Holml

期刊:Diabetologia

A perturbed serum lipidome has been detected in children and NOD mice who later develop type 1 diabetes. However, there is a lack of studies looking at pancreas lipid composition in relation to type 1 diabetes. We have previously shown that individuals with newly diagnosed type 1 diabetes have abnormal islet sphingolipid metabolism. In this study, we sought to further investigate the effects of fenofibrate, a regulator of lipid metabolism that has previously been shown to prevent diabetes and inflammation in the pancreas of NOD mice. Using MS, we found that fenofibrate treatment led to a specific increase in very-long-chain sphingolipids, predominantly C24. We observed no change in total ceramide levels, as the increase in C24 was associated with a corresponding decrease in C16 and C18. The altered chain length composition is critical, as the proapoptotic properties of ceramide are greatly dependent on the length of the lipid chain. C24 ceramide is an important component of myelin sheaths with essential roles in neuronal and metabolic health, whereas C16 ceramide promotes apoptosis and is associated with mitochondrial dysfunction and insulin resistance. Hence, our results suggest that fenofibrate creates a more beneficial ceramide composition in the pancreas. The function of sulfatide is equally dependent on lipid chain length, with C16 regulating insulin secretion and proinsulin folding, while C24 is an immune regulator. Furthermore, C24:1 sulfatide has been shown to induce transcription of the gene encoding indoleamine 2,3-dioxygenase 1, an important regulator of autoimmunity with reduced expression in individuals with newly diagnosed type 1 diabetes. The increase in C24:0 and C24:1 sulfatide is, thus, likely to create a more anti-inflammatory environment. This increase might be a direct explanation for the diabetes-protective effect of fenofibrate, as injections of C24:0 sulfatide have been shown to reduce diabetes incidence in NOD mice. The progression into diabetes is associated with decreased levels of GPLs in NOD mice, suggesting that the reduced level of GPLs in fenofibrate-treated mice might be disadvantageous. On the other hand, we found increased amounts of lysoGPL, of which LPC is an inducer of insulin secretion. The increased PC:PE ratio signals a changed membrane permeability, which could influence cytokine signalling; however, an increased ratio is also linked to endoplasmic reticulum stress. A limitation of this study is the lack of a ‘normal’ pancreatic lipidome from non-diabetic mice, thus making the global biological effects of the observed changes hard to predict. It is difficult to find an appropriate control as different mouse strains have very different pancreatic lipidomes. A recent study found that the genetically closely related NODSCID mouse (which does not develop diabetes) has a very different pancreatic lipidome to the NOD mouse, making it a bad model with which to compare. We are therefore at high risk of drawing different conclusions depending on which mouse strain we define as ‘normal’.

译文

已经在儿童和后来发展为1型糖尿病的NOD小鼠中检测到扰动的血清脂质组。然而,缺乏关于与1型糖尿病相关的胰腺脂质组成的研究。我们先前已经表明,新诊断的1型糖尿病患者的胰岛鞘脂代谢异常。在这项研究中,我们试图进一步研究非诺贝特的作用,非诺贝特是脂质代谢的调节剂,之前已被证明可预防NOD小鼠胰腺的糖尿病和炎症。使用MS,我们发现非诺贝特治疗导致非常长链鞘脂的特异性增加,主要是C24。我们观察到总神经酰胺水平没有变化,因为C24的增加与C16和C18的相应减少相关。改变的链长组成是关键的,因为神经酰胺的促凋亡特性极大地取决于脂质链的长度。 C24神经酰胺是髓鞘的重要成分,在神经元和代谢健康中具有重要作用,而C16神经酰胺促进细胞凋亡,并与线粒体功能障碍和胰岛素抵抗有关。因此,我们的结果表明非诺贝特在胰腺中产生更有益的神经酰胺组合物。硫苷脂的功能同样取决于脂质链长度,C16调节胰岛素分泌和胰岛素原折叠,而C24是免疫调节剂。此外,已显示C24:1硫苷脂诱导编码吲哚胺2,3-双加氧酶1的基因的转录,吲哚胺2,3-双加氧酶1是具有新诊断的1型糖尿病的个体中表达降低的自身免疫的重要调节剂。因此,C24:0和C24:1硫苷脂的增加可能产生更多的抗炎环境。这种增加可能是非诺贝特对糖尿病保护作用的直接解释,因为已注射C24:0硫苷脂可降低NOD小鼠的糖尿病发病率。进展为糖尿病与NOD小鼠中GPL水平降低相关,表明非诺贝特治疗小鼠中GPL水平降低可能是不利的。另一方面,我们发现lysoGPL的量增加,其中LPC是胰岛素分泌的诱导物。增加的PC:PE比率表明膜透性改变,这可能影响细胞因子信号传导;然而,增加的比例也与内质网应激有关。该研究的局限性是缺乏来自非糖尿病小鼠的“正常”胰腺脂质组,因此使观察到的变化的全局生物学效应难以预测。由于不同的小鼠品系具有非常不同的胰脂质组,因此难以找到合适的对照。最近的一项研究发现,遗传上密切相关的NODSCID小鼠(不会患糖尿病)与NOD小鼠的胰脂质组非常不同,这使得它成为一个可以比较的坏模型。因此,根据我们定义为“正常”的小鼠品系,我们很有可能得出不同的结论。