Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin.
Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin.
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DOI：
10.1038/nm.3372
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发表时间：
2013-12
期刊：
影响因子：
82.9
通讯作者：
Steinberg GR
中科院分区：
文献类型：
--
作者：
Fullerton MD;Galic S;Marcinko K;Sikkema S;Pulinilkunnil T;Chen ZP;O'Neill HM;Ford RJ;Palanivel R;O'Brien M;Hardie DG;Macaulay SL;Schertzer JD;Dyck JR;van Denderen BJ;Kemp BE;Steinberg GR
肥胖症的流行导致非酒精性脂肪性肝病(NAFLD)和2型糖尿病的发病率增加。AMP激活的蛋白激酶(AMPK)调节能量动态平衡，并被细胞应激、激素和广泛使用的抗2型糖尿病药物二甲双胍激活。AMPK在Ser79和Ser212分别磷酸化小鼠乙酰辅酶A羧化酶(ACC)1和Acc2，抑制乙酰辅酶A向丙二酰辅酶A的转化，丙二酰辅酶A是脂肪酸合成的前体，也是脂肪酸运输到线粒体进行氧化的变构抑制剂。为了测试这些磷酸化事件的生理影响，我们产生了在Acc1(Ser79)和Acc2(Ser212)(ACC双重敲入，AccDKI)都有丙氨酸敲入突变的小鼠。与野生型(WT)小鼠相比，这些小鼠的脂肪生成增加，脂肪酸氧化减少，这有助于胰岛素抵抗、葡萄糖耐量异常和NAFLD的进展，但不会导致肥胖。值得注意的是，通过高脂饮食造成肥胖的AccDKI小鼠，对二甲双胍的降脂和胰岛素增敏作用无效。这些发现证实，AMPK对ACC的抑制磷酸化对于控制脂代谢以及在肥胖的背景下对于二甲双胍诱导的胰岛素作用的改善是必不可少的。
The obesity epidemic has led to an increased incidence of non–alcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP–activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed anti–type 2 diabetic drug metformin. Ampk phosphorylates murine acetyl–CoA carboxylase (Acc) 1 at Ser79 and Acc2 at Ser212, inhibiting the conversion of acetyl–CoA to malonyl–CoA, a precursor in fatty acid synthesis as well as an allosteric inhibitor of fatty acid transport into mitochondria for oxidation. To test the physiological impact of these phosphorylation events we generated mice with alanine knock–in mutations in both Acc1 (Ser79) and Acc2 (Ser212) (Acc double knock–in, AccDKI). These mice have elevated lipogenesis and lower fatty acid oxidation compared to wild–type (WT) mice, which contribute to the progression of insulin resistance, glucose intolerance and NAFLD, but not obesity. Remarkably, AccDKI mice made obese by high–fat feeding, are refractory to the lipid–lowering and insulin–sensitizing effects of metformin. These findings establish that inhibitory phosphorylation of Acc by Ampk is essential for the control of lipid metabolism, and in the setting of obesity, for metformin–induced improvements in insulin action.