A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.
A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.
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DOI：
10.1038/nm.4057
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发表时间：
2016-04
期刊：
影响因子：
82.9
通讯作者：
Arany Z
中科院分区：
文献类型：
--
作者：
Jang C;Oh SF;Wada S;Rowe GC;Liu L;Chan MC;Rhee J;Hoshino A;Kim B;Ibrahim A;Baca LG;Kim E;Ghosh CC;Parikh SM;Jiang A;Chu Q;Forman DE;Lecker SH;Krishnaiah S;Rabinowitz JD;Weljie AM;Baur JA;Kasper DL;Arany Z
流行病学和实验数据暗示支链氨基酸（BCAAs）在胰岛素抵抗的发展，但这种联系的机制仍不清楚。骨骼肌中的胰岛素抵抗源于脂质物质的过度积累，这一过程需要血液中的脂质首先穿过血管壁。然而，很少有人知道这种跨内皮运输是如何发生或调节的。在这里，我们利用PGC-1α，一种调节FA消耗的广泛程序的转录共激活因子，来鉴定3-羟基异丁酸（3-HIB），BCAA缬氨酸的分解代谢中间体，作为跨内皮脂肪酸（FA）转运的新型旁分泌调节剂。3-HIB由肌肉细胞分泌，激活内皮FA转运，在体内刺激肌肉FA摄取，并促进动物肌肉脂质积聚和胰岛素抵抗。相反，抑制肌肉细胞中3-HIB的合成会阻断内皮FA摄取的促进作用。3-来自db/db小鼠和患有糖尿病的受试者的肌肉中的HIB水平升高。因此，这些数据揭示了一种调节FA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物，将FA通量的调节与BCAA分解代谢联系起来，并为BCAA分解代谢通量增加如何导致糖尿病提供了机制解释。
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 leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.