The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.
The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.
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DOI：
10.1016/j.cell.2016.05.071
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发表时间：
2016-07-14
期刊：
影响因子：
64.5
通讯作者：
Spiegelman BM
中科院分区：
文献类型：
--
作者：
Long JZ;Svensson KJ;Bateman LA;Lin H;Kamenecka T;Lokurkar IA;Lou J;Rao RR;Chang MR;Jedrychowski MP;Paulo JA;Gygi SP;Griffin PR;Nomura DK;Spiegelman BM
棕色和米色脂肪细胞是表达UCP1并将化学能作为热量耗散的特化细胞。这些细胞可能具有替代的UCP1独立产热机制。在这里，我们确定了分泌的酶，肽酶M20域包含1（PM20D1），这是丰富的UCP1+与UCP1-脂肪细胞。我们证明，PM20D1是一个双向酶在体外，催化脂肪酸和氨基酸的缩合生成N-酰基氨基酸，也逆水解反应。N-酰基氨基酸直接结合线粒体，并作为UCP1非依赖性呼吸的内源性解偶联剂发挥作用。循环PM20D1增加的小鼠呼吸增强，血液中的N-酰基氨基酸增加。最后，向小鼠施用N-酰基氨基酸改善葡萄糖稳态并增加能量消耗。这些数据确定了一个酶节点和一个家族的代谢产物，调节能量稳态，这条途径可能是有用的治疗肥胖症和相关疾病。米色脂肪细胞分泌一种酶，将脂质固定在负责直接授权线粒体产热的氨基酸上。
Brown and beige adipocytes are specialized cells that express UCP1 and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1+ versus UCP1- adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis; this pathway might be useful for treating obesity and associated disorders. Beige fat cells secrete an enzyme that tacks lipids onto amino acids responsible for directly licensing mitochondria for thermogenesis.