Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury.
Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury.
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DOI：
10.1016/j.cmet.2016.11.005
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发表时间：
2017-02-07
期刊：
影响因子：
29
通讯作者：
Tian R
中科院分区：
文献类型：
--
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
支链氨基酸（BCAAs）水平的升高最近被认为与心血管和代谢性疾病的发生有关，但其分子机制尚不清楚。在BCAA分解代谢受损的小鼠模型中，我们发现BCAAs的慢性积累抑制了葡萄糖代谢并使心脏对缺血性损伤敏感。高水平的BCAAs通过抑制丙酮酸脱氢酶复合物（PDH）活性选择性地破坏线粒体丙酮酸利用。此外，KO心脏中己糖胺生物合成途径的下调降低了蛋白o -链接- n -乙酰氨基葡萄糖（O-GlcNAc）修饰和失活的PDH，导致葡萄糖氧化显著降低。虽然KO的代谢重塑不影响心脏的基线能量和功能，但它使心脏容易受到缺血再灌注损伤。通过在KO心脏中过度表达GLUT1来促进BCAA分解代谢或使葡萄糖利用正常化，挽救了代谢和功能结果。这些观察结果揭示了BCAA分解代谢在调节心脏代谢和应激反应中的新作用。支链氨基酸（BCAAs）与心血管疾病有关。Li等人现在揭示了BCAA分解代谢调节心脏代谢和应激反应的分子机制。BCAAs的长期积累下调了己糖胺生物合成途径，使丙酮酸脱氢酶失活，使心脏容易受到缺血性损伤。
Elevated levels of branched-chain amino acids (BCAAs) have recently been implicated in the development of cardiovascular and metabolic diseases but the molecular mechanisms are unknown. In a mouse model of impaired BCAA catabolism (KO), we found that chronic accumulation of BCAAs suppressed glucose metabolism and sensitized the heart to ischemic injury. High levels of BCAAs selectively disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity. Furthermore, downregulation of hexosamine biosynthetic pathway in KO hearts decreased protein O-linked-N-acetylglucosamine (O-GlcNAc) modification and inactivated PDH resulting in significant decreases in glucose oxidation. Although the metabolic remodeling in KO did not affect baseline cardiac energetics or function, it rendered the heart vulnerable to ischemia-reperfusion injury. Promoting BCAA catabolism or normalizing glucose utilization by overexpressing GLUT1 in the KO heart rescued the metabolic and functional outcome. These observations revealed a novel role of BCAA catabolism in regulating cardiac metabolism and stress response. Branched-chain amino acids (BCAAs) have been implicated in cardiovascular disease. Li, et al now reveal molecular mechanisms behind BCAA catabolism in regulating cardiac metabolism and stress response. Chronic accumulation of BCAAs downregulates the hexosamine biosynthetic pathway and inactivates pyruvate dehydrogenase, which renders the heart vulnerable to ischemic injury.