Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.
Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.
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DOI：
10.1038/s41467-021-21962-2
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发表时间：
2021-03-15
影响因子：
16.6
通讯作者：
McGarrah RW
中科院分区：
文献类型：
--
作者：
Walejko JM;Christopher BA;Crown SB;Zhang GF;Pickar-Oliver A;Yoneshiro T;Foster MW;Page S;van Vliet S;Ilkayeva O;Muehlbauer MJ;Carson MW;Brozinick JT;Hammond CD;Gimeno RE;Moseley MA;Kajimura S;Gersbach CA;Newgard CB;White PJ;McGarrah RW
支链氨基酸（BCAA）及其同源α-酮酸（BCKA）在一系列心脏代谢疾病中升高。在这里，我们证明了均匀13c标记的α-酮异戊酸（[U-13C]KIV）在心脏中的主要代谢命运是再分解为缬氨酸。BCKDH激酶抑制剂BT2对心脏支链α-酮酸脱氢酶（BCKDH）的激活不影响[U-13C]KIV对缬氨酸的强通量。BCAA和BCKA远离线粒体氧化可能是由于线粒体BCAA转运体SLC25A44在心脏中的低水平表达，因为其过表达显著降低了[U-13C]KIV中[13C]标记缬氨酸的积累。最后，在肥胖大鼠中发现，灌注心脏暴露于BCKA水平会增加翻译抑制因子4E-BP1的磷酸化以及MEK-ERK途径中的多种蛋白质，导致总蛋白质合成增加一倍。这些数据表明，肥胖患者BCKA水平升高可能通过慢性激活蛋白质合成导致病理性心脏肥厚。支链酮酸（BCKA）代谢的系统调节改变心脏健康。在这里，作者定义了BCKA在心脏中的主要命运，并证明急性暴露于肥胖中发现的BCKA水平激活了心脏蛋白质合成并显着改变了心脏磷蛋白质组。
Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-13C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [13C]-labeled valine from [U-13C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis. Systemic modulation of branched-chain keto acid (BCKA) metabolism alters cardiac health. Here, the authors define the major fates of BCKA in the heart and demonstrate that acute exposure to BCKA levels found in obesity activates cardiac protein synthesis and markedly alters the heart phosphoproteome.
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影响因子：
4.1
作者：
Eyers, CE;McNeill, H;Cohen, P
通讯作者：
Cohen, P
影响因子：
4.4
作者：
Foster MW;Gwinn WM;Kelly FL;Brass DM;Valente AM;Moseley MA;Thompson JW;Morgan DL;Palmer SM
通讯作者：
Palmer SM
影响因子：
11.4
作者：
Bueno, OF;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
29
作者：
Li T;Zhang Z;Kolwicz SC Jr;Abell L;Roe ND;Kim M;Zhou B;Cao Y;Ritterhoff J;Gu H;Raftery D;Sun H;Tian R
通讯作者：
Tian R
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