Abstract
Reduced availability of nitric oxide (NO) in the vasculature is a major factor contributing to the impaired action of insulin on blood flow and, therefore, insulin resistance in obese and diabetic subjects. Available evidence shows that vascular insulin resistance plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Interestingly, increased concentrations of l-leucine in the plasma occur in obese humans and other animals with vascular dysfunction. Among branched-chain amino acids, l-leucine is unique in inhibiting NO synthesis from l-arginine in endothelial cells and may modulate cardiovascular homeostasis in insulin resistance. Results of recent studies indicate that l-leucine is an activator of glutamine:fructose-6-phosphate aminotransferase (GFAT), which is the first and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, l-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells. We propose that reducing circulating levels of l-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects. Such means may include dietary supplementation with either α-ketoglutarate to enhance the catabolism of l-leucine in the small intestine and other tissues or with N-ethyl-l-glutamine to inhibit GFAT activity in endothelial cells. Preventing leucine-induced activation of GFAT by nutritional supplements or pharmaceutical drugs may contribute to improved cardiovascular function by enhancing vascular NO synthesis.
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Abbreviations
- BCAA:
-
Branched-chain amino acids
- BCAT:
-
Branched-chain amino acid transaminase
- BCKAD:
-
Branched-chain α-ketoacid dehydrogenase
- BH4:
-
(6R)-5,6,7,8-Tetrahydro-l-biopterin
- EDCF:
-
Endothelium-derived constricting factor
- EDRF:
-
Endothelium-derived relaxing factor
- FAD:
-
Flavin adenine dinucleotide
- FMN:
-
Flavin mononucleotide
- GFAT:
-
Glutamine:fructose-6-phosphate aminotransferase
- KIC:
-
α-Ketoisocaproate
- mTOR:
-
Mammalian target of rapamycin
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
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Acknowledgments
Work in our laboratories was supported by the National Basic Research Program of China (Grant 2013CB127302), the National Natural Science Foundation of China (No. 31172217, 31272451 and 31272450), American Heart Association (10GRNT4480020), and Texas A&M AgriLife Research (H-8200). Ying Yang was supported by a Fellowship from the Chinese Scholarship Council and National Natural Science Foundation of China (No. 31172225 and 31372327).
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Yang, Y., Wu, Z., Meininger, C.J. et al. l-Leucine and NO-mediated cardiovascular function. Amino Acids 47, 435–447 (2015). https://doi.org/10.1007/s00726-014-1904-y
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DOI: https://doi.org/10.1007/s00726-014-1904-y