SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.
SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.
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DOI：
10.1016/j.molcel.2013.05.012
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发表时间：
2013-06-06
期刊：
影响因子：
16
通讯作者：
Haigis, Marcia C.
中科院分区：
文献类型：
--
作者：
Laurent, Gaelle;German, Natalie J.;Saha, Asish K.;de Boer, Vincent C. J.;Davies, Michael;Koves, Timothy R.;Dephoure, Noah;Fischer, Frank;Boanca, Gina;Vaitheesvaran, Bhavapriya;Lovitch, Scott B.;Sharpe, Arlene H.;Kurland, Irwin J.;Steegborn, Clemens;Gygi, Steven P.;Muoio, Deborah M.;Ruderman, Neil B.;Haigis, Marcia C.
脂质代谢受到生物体营养状态的严格调控。营养丰富的条件会增加脂肪生成，而营养缺乏则促进脂肪氧化。在这项研究中，我们确定线粒体去乙酰化酶SIRT4是脂质内稳态的一种新型调节因子。SIRT4在营养充足的条件下具有活性，可抑制脂肪酸氧化，同时促进脂质合成代谢。SIRT4使丙二酸单酰辅酶A脱羧酶（MCD）去乙酰化并抑制其活性，MCD是一种将丙二酸单酰辅酶A转化为乙酰辅酶A的酶。丙二酸单酰辅酶A为脂肪生成提供碳骨架，同时也抑制脂肪氧化。缺乏SIRT4的小鼠在骨骼肌和白色脂肪组织中表现出MCD活性升高以及丙二酸单酰辅酶A降低。因此，SIRT4基因敲除小鼠表现出脂质代谢失调，导致运动耐力增强以及对饮食诱导肥胖的抵抗。总之，这项工作阐明了SIRT4是脂质内稳态的重要调节因子，确定MCD是SIRT4的一个新靶点，并加深了我们对丙二酸单酰辅酶A调节轴的理解。
Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a novel regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a novel SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.
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影响因子：
64.5
作者：
Narkar VA;Downes M;Yu RT;Embler E;Wang YX;Banayo E;Mihaylova MM;Nelson MC;Zou Y;Juguilon H;Kang H;Shaw RJ;Evans RM
通讯作者：
Evans RM
DOI：
10.1152/ajpendo.00341.2005
发表时间：
2006-06-01
影响因子：
5.1
作者：
Kuhl, Jeanette E.;Ruderman, Neil B.;Bavenholm, Peter N.
通讯作者：
Bavenholm, Peter N.
影响因子：
3.3
作者：
Hutber, CA;Rasmussen, BB;Winder, WW
通讯作者：
Winder, WW
影响因子：
64.8
作者：
Barber, Matthew F.;Michishita-Kioi, Eriko;Xi, Yuanxin;Tasselli, Luisa;Kioi, Mitomu;Moqtaderi, Zarmik;Tennen, Ruth I.;Paredes, Silvana;Young, Nicolas L.;Chen, Kaifu;Struhl, Kevin;Garcia, Benjamin A.;Gozani, Or;Li, Wei;Chua, Katrin F.
通讯作者：
Chua, Katrin F.
影响因子：
--
作者：
Lombard, David B;Tishkoff, Daniel X;Bao, Jianjun
通讯作者：
Bao, Jianjun