Substrate cycling between de novo lipogenesis and lipid oxidation:: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity
Substrate cycling between de novo lipogenesis and lipid oxidation:: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity
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DOI：
10.1038/sj.ijo.0802861
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发表时间：
2004-12-01
影响因子：
4.9
通讯作者：
Solinas, G
中科院分区：
文献类型：
--
作者：
Dulloo, AG;Gubler, M;Solinas, G
生命是一种燃烧，但是维持人类生命的主要燃料底物如何相互竞争和相互作用以燃烧，自从Randle在1963年提出“葡萄糖-脂肪酸循环”以来，一直是胰岛素抵抗发病机制研究的中心。从那时起，以葡萄糖和脂质代谢之间的互惠性和依赖性为特征的相互作用的几个特征已经被揭示，即：（i）高浓度脂肪酸对葡萄糖氧化的抑制作用（通过线粒体丙酮酸脱氢酶的失活或通过胰岛素介导的葡萄糖转运的脱敏），（ii）葡萄糖浓度升高对脂肪酸氧化的抑制作用（通过丙二酰辅酶A调节脂肪酸进入线粒体），以及最近的（iii）葡萄糖浓度升高对从头脂肪生成的刺激作用，即，从葡萄糖合成脂质（通过SREBP 1c调节糖酵解和脂肪生成酶）本文首先回顾了骨骼肌中葡萄糖和脂质之间的相互作用对血糖和肌细胞内脂质稳态的生理意义。然后，它集中在新兴的证据，从量热研究调查瘦素对完整骨骼肌产热的直接影响，葡萄糖和脂质氧化之间的相互作用的另一个特点：从头脂肪生成和脂质氧化之间的底物循环。有人提出，这种能量耗散基板循环，链接葡萄糖和脂质代谢产热可以作为一个“微调”机制，调节肌细胞内脂质稳态，因此有助于保护骨骼肌免受脂毒性。
Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:(i) the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation ( via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport),(ii) the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation ( via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently(iii) the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose ( via SREBP1c regulation of glycolytic and lipogenic enzymes).This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.