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首页> 外文学位 >A metabolite of branched chain amino acids drives vascular fatty acid transport and causes glucose intolerance.
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A metabolite of branched chain amino acids drives vascular fatty acid transport and causes glucose intolerance.

机译：支链氨基酸的代谢产物驱动血管脂肪酸运输并引起葡萄糖不耐症。

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摘要

Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear. Insulin resistance in skeletal muscle stems from excess accumulation of lipid species, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial transport of fatty acids. PGC-1alpha, a transcriptional co-activator that regulates broad programs of fatty acid consumption, induces the secretion from muscle of 3-HIB, which then triggers fatty acid uptake and transport in endothelial cells. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial fatty acid uptake. Providing animals with 3-HIB in drinking water, or inducing 3-HIB levels in skeletal muscle by over-expressing PGC-1alpha, stimulates muscle to take up fatty acids in vivo, leading to muscle lipid accumulation, and systemic glucose intolerance. 3-HIB levels are elevated in muscle from patients with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of fatty acids, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of fatty acid flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.
机译：流行病学和实验数据表明，支链氨基酸（BCAAs）参与了胰岛素抵抗的发展，但这种联系的机制尚不清楚。骨骼肌中的胰岛素抵抗源于脂质种类的过度积累，这一过程需要血液中的脂质首先穿过血管壁。然而，人们对这种跨内皮运输是如何发生或受到调控的了解甚少。在这里，我们确定3-羟基异丁酸酯（3-HIB），BCAA缬氨酸的分解代谢中间体，作为跨胆固醇运输脂肪酸的新型旁分泌调节剂。 PGC-1alpha是一种转录共激活因子，可调节广泛的脂肪酸消耗程序，可诱导3-HIB肌肉分泌，然后触发脂肪酸在内皮细胞中的摄取和转运。相反，抑制肌肉细胞中3-HIB的合成会阻止内皮脂肪酸的摄取。向动物提供饮用水中的3-HIB，或通过过度表达PGC-1alpha诱导骨骼肌中3-HIB的水平，刺激肌肉在体内吸收脂肪酸，导致肌肉脂质蓄积和全身性葡萄糖耐量下降。糖尿病患者肌肉中的3-HIB水平升高。因此，这些数据揭示了调节脂肪酸跨内皮通量的新机制，揭示了3-HIB作为一种新的生物活性信号代谢产物，将脂肪酸通量的调节与BCAA分解代谢联系起来，并提供了有关如何增加BCAA分解代谢通量的机理解释。引起糖尿病。

著录项

  • 作者

    Jang, Cholsoon.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 143 p.
  • 总页数 143
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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