Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.
Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.
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DOI：
10.2337/db13-1070
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发表时间：
2015-01
期刊：
影响因子：
7.7
通讯作者：
Coleman RA
中科院分区：
文献类型：
--
作者：
Li LO;Grevengoed TJ;Paul DS;Ilkayeva O;Koves TR;Pascual F;Newgard CB;Muoio DM;Coleman RA
骨骼肌在脂肪酸（FA）和葡萄糖氧化之间转换的能力受损与代谢稳态紊乱有关。为了了解肌肉FA氧化如何影响全身葡萄糖，我们研究了骨骼肌特异性长链酰基辅酶A合成酶（ACSL）1缺乏的小鼠。ACSL 1缺乏导致ACSL特异性活性损失91%，肌肉FA氧化减少60-85%。Acsl 1 M −/−小鼠对胰岛素更敏感，在整夜禁食期间，它们的呼吸交换率更高，表明葡萄糖使用量更大。在耐力运动中，Acsl 1 M −/−小鼠只跑了对照组的48%。当Acsl 1 M −/−小鼠筋疲力尽，而对照组小鼠继续跑步时，两种基因型的肝脏和肌肉糖原以及三酰甘油储存量相似;然而，Acsl 1 M −/−小鼠的血糖浓度为1.40 mg/dL，而对照组的血糖浓度为1.90 mg/dL。过量使用葡萄糖和可能使用氨基酸作为肌肉内的燃料，耗尽了葡萄糖储备，降低了肝再生的底物可用性。令人惊讶的是，肌肉酰基辅酶A的含量在力竭时显著升高，表明由其他ACSL同种型合成的酰基辅酶A不能用于β-氧化。这种酰基辅酶A的区室化导致了过度的葡萄糖需求和严重损害的全身葡萄糖稳态。
The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle–specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60–85% decrease in muscle FA oxidation. Acsl1M−/− mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1M−/− mice ran only 48% as far as controls. At the time that Acsl1M−/− mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1M−/− mice were ∼40 mg/dL, whereas glucose concentrations in controls were ∼90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis.
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DOI：
10.1016/j.bbalip.2009.09.024
发表时间：
2010-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Li LO;Klett EL;Coleman RA
通讯作者：
Coleman RA
影响因子：
3.7
作者：
Leonardi R;Rehg JE;Rock CO;Jackowski S
通讯作者：
Jackowski S
影响因子：
4.5
作者：
Ferrara CT;Wang P;Neto EC;Stevens RD;Bain JR;Wenner BR;Ilkayeva OR;Keller MP;Blasiole DA;Kendziorski C;Yandell BS;Newgard CB;Attie AD
通讯作者：
Attie AD
影响因子：
7.7
作者：
Kelley, DE;Mandarino, LJ
通讯作者：
Mandarino, LJ
DOI：
10.1152/ajpendo.00399.2006
发表时间：
2007-10-01
影响因子：
5.1
作者：
Noland, Robert C.;Woodlief, Tracey L.;Cortright, Ronald N.
通讯作者：
Cortright, Ronald N.