Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats
Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats
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DOI：
10.1152/ajpendo.00334.2019
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发表时间：
2020-02-01
影响因子：
5.1
通讯作者：
Newgard, Christopher B.
中科院分区：
文献类型：
--
作者：
McGarrah, Robert W.;Zhang, Guo-Fang;Newgard, Christopher B.
支链氨基酸（BCAA）循环水平的升高与多种心脏代谢疾病和病症相关。在啮齿动物肥胖模型中限制饮食BCAA降低了循环BCAA水平，改善了整个动物和肌肉胰岛素敏感性和脂质稳态，但BCAA供应对心脏代谢的影响尚未研究。在这里，我们报告说，喂养支链氨基酸限制的食物饮食Zucker脂肪大鼠（ZFR）的心脏燃料代谢的转变，有利于脂肪酸相对于葡萄糖catabolites。这通过来自[1-C-13]棕榈酸酯的乙酰辅酶A标记的增加和来自[U-C-13]葡萄糖的乙酰辅酶A和丙二酰辅酶A标记的减少来说明，伴随着心脏己糖激酶II和葡萄糖转运蛋白4蛋白水平的降低。心脏组织的代谢组学分析支持这些发现，证明了在ZFR和Zucker瘦大鼠（ZLR）的心脏中的一系列脂肪酸衍生代谢物的水平增加，这些大鼠喂食限制支链氨基酸的饮食。此外，与普通饲料喂养的ZLR相比，ZFR中心脏甘油三酯储存的两倍增加在BCAA限制饮食喂养的ZFR中消除。最后，支链酮酸脱氢酶（BCKDH）的酶活性不受BCAA限制的影响，心脏中BCAA的水平反映了它们在循环中的水平。总之，减少BCAA供应肥胖改善心脏代谢健康的机制独立于BCKDH活性的改变。
Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-C-13]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-C-13]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.