Montgomery Magdalene K, Brown Simon H J, Lim Xin Y, Fiveash Corrine E, Osborne Brenna, Bentley Nicholas L, Braude Jeremy P, Mitchell Todd W, Coster Adelle C F, Don Anthony S, Cooney Gregory J, Schmitz-Peiffer Carsten, Turner Nigel
Department of Pharmacology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.
School of Medicine, University of Wollongong, Wollongong, NSW, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
Biochim Biophys Acta. 2016 Nov;1861(11):1828-1839. doi: 10.1016/j.bbalip.2016.08.016. Epub 2016 Aug 31.
In a recent study, we showed that in response to high fat feeding C57BL/6, 129X1, DBA/2 and FVB/N mice all developed glucose intolerance, while BALB/c mice displayed minimal deterioration in glucose tolerance and insulin action. Lipidomic analysis of livers across these five strains has revealed marked strain-specific differences in ceramide (Cer) and sphingomyelin (SM) species with high-fat feeding; with increases in C16-C22 (long-chain) and reductions in C>22 (very long-chain) Cer and SM species observed in the four strains that developed HFD-induced glucose intolerance. Intriguingly, the opposite pattern was observed in sphingolipid species in BALB/c mice. These strain-specific changes in sphingolipid acylation closely correlated with ceramide synthase 2 (CerS2) protein content and activity, with reduced CerS2 levels/activity observed in glucose intolerant strains and increased content in BALB/c mice. Overexpression of CerS2 in primary mouse hepatocytes induced a specific elevation in very long-chain Cer, but despite the overall increase in ceramide abundance, there was a substantial improvement in insulin signal transduction, as well as decreased ER stress and gluconeogenic markers. Overall our findings suggest that very long-chain sphingolipid species exhibit a protective role against the development of glucose intolerance and hepatic insulin resistance.
在最近的一项研究中，我们发现，高脂喂养时，C57BL/6、129X1、DBA/2和FVB/N小鼠均出现葡萄糖不耐受，而BALB/c小鼠的葡萄糖耐量和胰岛素作用仅有轻微恶化。对这五个品系小鼠肝脏进行的脂质组学分析显示，高脂喂养后，神经酰胺（Cer）和鞘磷脂（SM）种类存在明显的品系特异性差异；在出现高脂饮食诱导的葡萄糖不耐受的四个品系中，观察到C16 - C22（长链）神经酰胺和鞘磷脂增加，C>22（超长链）神经酰胺和鞘磷脂减少。有趣的是，在BALB/c小鼠的鞘脂种类中观察到相反的模式。鞘脂酰化的这些品系特异性变化与神经酰胺合酶2（CerS2）的蛋白质含量和活性密切相关，在葡萄糖不耐受的品系中观察到CerS2水平/活性降低，而在BALB/c小鼠中含量增加。在原代小鼠肝细胞中过表达CerS2会导致超长链神经酰胺特异性升高，尽管神经酰胺丰度总体增加，但胰岛素信号转导有显著改善，同时内质网应激和糖异生标志物减少。总体而言，我们的研究结果表明，超长链鞘脂种类对葡萄糖不耐受和肝脏胰岛素抵抗的发展具有保护作用。
