The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.
The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.
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DOI：
10.1016/j.cmet.2018.04.015
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发表时间：
2018-06-05
期刊：
影响因子：
29
通讯作者：
Newgard CB
中科院分区：
文献类型：
--
作者：
White PJ;McGarrah RW;Grimsrud PA;Tso SC;Yang WH;Haldeman JM;Grenier-Larouche T;An J;Lapworth AL;Astapova I;Hannou SA;George T;Arlotto M;Olson LB;Lai M;Zhang GF;Ilkayeva O;Herman MA;Wynn RM;Chuang DT;Newgard CB
支链氨基酸（BCAA）与糖脂代谢失调密切相关，但其潜在机制尚不清楚。我们报告说，抑制激酶（BDK）或磷酸酶（PPM 1 K）的过度表达，调节支链酮酸脱氢酶（BCKDH），BCAA催化剂的承诺步骤，降低循环BCAA，减少肝脂肪变性和改善葡萄糖耐量在Zucker脂肪大鼠体重减轻的情况下。磷酸化蛋白质组学分析确定ATP-柠檬酸裂解酶（ACL）作为BDK和PPM 1 K的替代底物。BDK的肝脏过表达增加了ACL磷酸化并激活了从头脂肪生成。BDK和PPM 1 K转录水平分别增加和抑制，以响应果糖喂养或ChREBP-β转录因子的表达。这些研究将BDK和PPM 1 K确定为整合BCAA和脂质代谢的ChREBP调节节点。此外，在严重肥胖的遗传模型中，BDK：PPM 1 K比率的操纵减轻了关键的代谢疾病表型。支链氨基酸（BCAA）与代谢性疾病密切相关。白色等人证明，调节限速BCAA代谢酶BCKDH的激酶（BDK）和磷酸酶（PPM 1 K）也调节ATP-柠檬酸裂解酶（一种关键的脂肪生成酶），从而确定了整合BCAA和脂质代谢的新调节节点。
Branched chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulate branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity. Branched-chain amino acids (BCAA) are strongly associated with metabolic diseases. White et al. demonstrate that the kinase (BDK) and phosphatase (PPM1K) that regulate a rate-limiting BCAA metabolic enzyme, BCKDH, also regulate ATP-citrate lyase, a key lipogenic enzyme, thus identifying a new regulatory node that integrates BCAA and lipid metabolism.
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影响因子：
8.2
作者：
Glynn EL;Piner LW;Huffman KM;Slentz CA;Elliot-Penry L;AbouAssi H;White PJ;Bain JR;Muehlbauer MJ;Ilkayeva OR;Stevens RD;Porter Starr KN;Bales CW;Volpi E;Brosnan MJ;Trimmer JK;Rolph TP;Newgard CB;Kraus WE
通讯作者：
Kraus WE
DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
15.9
作者：
Lu, Gang;Sun, Haipeng;Wang, Yibin
通讯作者：
Wang, Yibin
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
DOI：
10.1073/pnas.0401516101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Iizuka, K;Bruick, RK;Uyeda, K
通讯作者：
Uyeda, K