Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver
Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver
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DOI：
10.1073/pnas.0401627101
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发表时间：
2004-04-27
影响因子：
11.1
通讯作者：
Ntambi, JM
中科院分区：
文献类型：
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作者：
Dobrzyn, P;Dobrzyn, A;Ntambi, JM
硬脂酰辅酶A去饱和酶（SCD）催化单不饱和脂肪酸生物合成中的限速步骤。具有SCD 1同种型的靶向破坏的小鼠具有减少的身体肥胖、增加的能量消耗和肝脏中编码脂肪酸β-氧化酶的几种基因的上调表达。SCD缺陷导致这些代谢变化的机制目前尚不清楚。在此，我们发现在能量消耗增加时调节脂质代谢的代谢传感器AMP活化蛋白激酶（AMPK）的磷酸化和活性在SCD 1基因敲除小鼠（SCD 1-/-）的肝脏中显著增加（约40%，P < 0.01）。在AMPK激活的同时，乙酰辅酶A羧化酶Ser-79磷酸化水平升高，酶活性降低（约35%，P < 0.001），导致细胞内丙二酰辅酶A水平降低（约47%，P < 0.001）。在瘦素缺乏的ob/ob小鼠中，SCD 1突变也增加了AMPK磷酸化和活性，并增加了乙酰辅酶A羧化酶磷酸化。已知较低的丙二酰辅酶A浓度可使肉毒碱棕榈酰转移酶1（CPT 1）去抑制。在SCD 1-/-小鼠中，CPT 1和CPT 2活性显著增加（在两种情况下均接近60%，P < 0.001），从而刺激线粒体棕榈酰辅酶A的氧化。我们的研究结果确定AMPK作为增加脂肪酸氧化在SCD 1缺陷小鼠的肝脏介质。
Stearoyl-CoA desaturase (SCD) catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids. Mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased energy expenditure, and up-regulated expression of several genes encoding enzymes of fatty acid beta-oxidation in liver. The mechanisms by which SCD deficiency leads to these metabolic changes are presently unknown. Here we show that the phosphorylation and activity of AMP-activated protein kinase (AMPK), a metabolic sensor that regulates lipid metabolism during increased energy expenditure is significantly increased (approximate to40%, P < 0.01) in liver of SCD1 knockout mice (SCD1 -/-). In parallel with the activation of AMPK, the phosphorylation of acetyl-CoA carboxylase at Ser-79 was increased and enzymatic activity was decreased (approximate to35%, P < 0.001), resulting in decreased intracellular levels of malonyl-CoA (approximate to47%, P < 0.001). An SCD1 mutation also increased AMPK phosphorylation and activity and increased acetyl-CoA carboxylase phosphorylation in leptin-deficient ob/ob mice. Lower malonyl-CoA concentrations are known to derepress carnitine palmitoyltransferase 1 (CPT1). In SCD1-/- mice, CPT1 and CPT2 activities were significantly increased (in both cases approximate to60%, P < 0.001) thereby stimulating the oxidation of mitochondrial palmitoyl-CoA. Our results identify AMPK as a mediator of increased fatty acid oxidation in liver of SCD1-deficient mice.