Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance
Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance
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DOI：
10.1152/ajpendo.90287.2008
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发表时间：
2008-09-01
影响因子：
5.1
通讯作者：
DeFronzo, Ralph A.
中科院分区：
文献类型：
--
作者：
Abdul-Ghani, Muhammad A.;Muller, Florian L.;DeFronzo, Ralph A.
胰岛素抵抗是2型糖尿病和肥胖的特征。胰岛素抵抗个体表现出游离脂肪酸（FFA）代谢的多种紊乱，并在胰岛素靶组织中有过度的脂质蓄积。尽管许多证据支持FFA代谢改变在胰岛素抵抗的发展中的因果作用，即，关于“脂毒性”，升高的血浆FFA水平引起胰岛素抵抗的细胞内机制尚未完全阐明。最近的研究表明，线粒体功能障碍可能在骨骼肌胰岛素抵抗的发病机制中发挥作用。我们研究了FFA代谢产物[棕榈酰肉毒碱（PC），棕榈酰辅酶A（CoA），油酰辅酶A]对从小鼠和人骨骼肌中分离的线粒体中ATP合成的影响。在0.5至2 μ M的浓度范围内，这些FFA代谢物刺激ATP合成，然而，高于5 μ M，有ATP合成的剂量反应抑制。此外，10 μ M PC抑制丙酮酸合成ATP。升高的PC浓度（>= 10 μ M）抑制电子传递链的活性，降低线粒体内膜电位。这些获得性线粒体缺陷，由FFA代谢物浓度的生理增加引起，提供了脂毒性，线粒体功能障碍和肌肉胰岛素抵抗之间的机制联系。
Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., "lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 mu M, these FFA metabolites stimulated ATP synthesis; however, above 5 mu M, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 mu M PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (>= 10 mu M) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.