Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes.
Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes.
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DOI：
10.1186/s13073-015-0179-6
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发表时间：
2015
期刊：
影响因子：
12.3
通讯作者：
Griffin JL
中科院分区：
文献类型：
--
作者：
Eiden M;Koulman A;Hatunic M;West JA;Murfitt S;Osei M;Adams C;Wang X;Chu Y;Marney L;Roberts LD;O'Rahilly S;Semple RK;Savage DB;Griffin JL
最近几项代谢组学研究的证据表明，含有较短(14-16个碳原子)的三酰甘油的饱和脂肪酸浓度增加与胰岛素抵抗和2型糖尿病的风险有关。虽然不能从关联研究中推断因果关系，但可以从基因上确定胰岛素抵抗主要原因的患者提供了独特的机会来应对这一挑战。我们比较了先天性脂肪营养不良或功能丧失的胰岛素抵抗(INSR)基因突变患者与健康对照组的代谢物特征。在INSR组中，三酰甘油的种类没有显著差异，这表明以前在流行病学研究中观察到的变化并不纯粹是胰岛素抵抗的结果。脂肪营养不良患者体内碳数较低、饱和度较高的三酰甘油的存在提示，这些代谢物的变化可能与原发性脂肪组织功能障碍有关。观察到的三酰甘油种类表明肝脏中新生脂肪生成增加。为了验证这一点，我们在质谱分析之前，使用尺寸排阻色谱研究了这些三酰甘油在脂蛋白组分中的分布。这将这些三酰甘油与非常低密度的脂蛋白颗粒联系在一起，从而将三酰甘油从肝脏释放到血液中。为了进一步测试这些三酰甘油的肝脏来源，我们在小鼠中诱导了从头脂肪生成，比较了饮食或高脂肪饮食中ob/ob和野生型小鼠，证实了从头脂肪生成诱导了相对较短、更饱和的脂肪酸的增加。总体而言，这些研究强调，在能量摄入超过脂肪组织能力的状态下，肝脏新生脂肪生成在代谢性血脂异常的发病机制中起作用。本文的在线版本(doi：10.1186/s13073-015-0179-6)包含补充材料，授权用户可以使用。
Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14–16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Although causality cannot be inferred from association studies, patients in whom the primary cause of insulin resistance can be genetically defined offer unique opportunities to address this challenge. We compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR gene) mutations with healthy controls. The absence of significant differences in triacylglycerol species in the INSR group suggest that changes previously observed in epidemiological studies are not purely a consequence of insulin resistance. The presence of triacylglycerols with lower carbon numbers and high saturation in patients with lipodystrophy suggests that these metabolite changes may be associated with primary adipose tissue dysfunction. The observed pattern of triacylglycerol species is indicative of increased de novo lipogenesis in the liver. To test this we investigated the distribution of these triacylglycerols in lipoprotein fractions using size exclusion chromatography prior to mass spectrometry. This associated these triacylglycerols with very low-density lipoprotein particles, and hence release of triacylglycerols into the blood from the liver. To test further the hepatic origin of these triacylglycerols we induced de novo lipogenesis in the mouse, comparing ob/ob and wild-type mice on a chow or high fat diet, confirming that de novo lipogenesis induced an increase in relatively shorter, more saturated fatty acids. Overall, these studies highlight hepatic de novo lipogenesis in the pathogenesis of metabolic dyslipidaemia in states where energy intake exceeds the capacity of adipose tissue. The online version of this article (doi:10.1186/s13073-015-0179-6) contains supplementary material, which is available to authorized users.