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The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jun-05 , DOI: 10.1016/j.cmet.2018.04.015 Phillip J White 1 , Robert W McGarrah 1 , Paul A Grimsrud 2 , Shih-Chia Tso 3 , Wen-Hsuan Yang 2 , Jonathan M Haldeman 2 , Thomas Grenier-Larouche 2 , Jie An 2 , Amanda L Lapworth 2 , Inna Astapova 1 , Sarah A Hannou 2 , Tabitha George 2 , Michelle Arlotto 2 , Lyra B Olson 2 , Michelle Lai 4 , Guo-Fang Zhang 1 , Olga Ilkayeva 2 , Mark A Herman 1 , R Max Wynn 3 , David T Chuang 3 , Christopher B Newgard 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jun-05 , DOI: 10.1016/j.cmet.2018.04.015 Phillip J White 1 , Robert W McGarrah 1 , Paul A Grimsrud 2 , Shih-Chia Tso 3 , Wen-Hsuan Yang 2 , Jonathan M Haldeman 2 , Thomas Grenier-Larouche 2 , Jie An 2 , Amanda L Lapworth 2 , Inna Astapova 1 , Sarah A Hannou 2 , Tabitha George 2 , Michelle Arlotto 2 , Lyra B Olson 2 , Michelle Lai 4 , Guo-Fang Zhang 1 , Olga Ilkayeva 2 , Mark A Herman 1 , R Max Wynn 3 , David T Chuang 3 , Christopher B Newgard 1
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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 regulates 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.
中文翻译：
BCKDH 激酶和磷酸酶通过调节 ATP-柠檬酸裂解酶整合 BCAA 和脂质代谢。
支链氨基酸 (BCAA) 与葡萄糖和脂质代谢失调密切相关，但其潜在机制却知之甚少。我们报告抑制激酶 (BDK) 或调节支链酮酸脱氢酶 (BCKDH) 的磷酸酶 (PPM1K) 过表达，这是 BCAA 分解代谢的关键步骤，降低循环 BCAA，减少肝脂肪变性，并改善葡萄糖耐量Zucker 脂肪大鼠没有体重减轻。磷酸蛋白质组学分析确定 ATP-柠檬酸裂解酶 (ACL) 是 BDK 和 PPM1K 的替代底物。BDK 的肝过表达增加了 ACL 磷酸化并激活了从头脂肪生成。BDK 和 PPM1K 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 PPM1K 确定为整合 BCAA 和脂质代谢的 ChREBP 调节节点。此外，操纵 BDK:PPM1K 比率可减轻严重肥胖遗传模型中的关键代谢疾病表型。
更新日期：2018-05-17
中文翻译：
BCKDH 激酶和磷酸酶通过调节 ATP-柠檬酸裂解酶整合 BCAA 和脂质代谢。
支链氨基酸 (BCAA) 与葡萄糖和脂质代谢失调密切相关，但其潜在机制却知之甚少。我们报告抑制激酶 (BDK) 或调节支链酮酸脱氢酶 (BCKDH) 的磷酸酶 (PPM1K) 过表达，这是 BCAA 分解代谢的关键步骤，降低循环 BCAA，减少肝脂肪变性，并改善葡萄糖耐量Zucker 脂肪大鼠没有体重减轻。磷酸蛋白质组学分析确定 ATP-柠檬酸裂解酶 (ACL) 是 BDK 和 PPM1K 的替代底物。BDK 的肝过表达增加了 ACL 磷酸化并激活了从头脂肪生成。BDK 和 PPM1K 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 PPM1K 确定为整合 BCAA 和脂质代谢的 ChREBP 调节节点。此外，操纵 BDK:PPM1K 比率可减轻严重肥胖遗传模型中的关键代谢疾病表型。
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