Abstract：Abstract As an important signaling molecular, branch chain amino acids (BCAA) participate the synthesis and catabolism of protein of amino acids, and regulate food intake et al. in animal body. These processes include two conservative signaling pathway, one is the mammals target of rapamycin (mTOR) which sense of amino acid abundance, and another is the general amino acid control non-derepressible 2 (GCN2) which sense the absence of one or more amino acids by virtue of direct binding to uncharged tRNAs. This review mainly focused on the effect of BCAA on mTOR and GCN2 signaling pathway to further elucidate how BCAAs are involved in protein synthesis and catabolism. This review provides a reference for the study of protein turnover regulation in mammalian and gives a theoretical basis for BCAA application in feed additives.
[1]Anthony, T.G., B. J. Mcdaniel, R. L. Byerley, et al. 2004. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. Journal of Biological Chemistry 279(35):36553-36561. [2]Appuhamy, J.A., N. A. Knoebel, W. A. Nayananjalie, et al. 2012. Isoleucine and leucine independently regulate mTOR signaling and protein synthesis in MAC-T cells and bovine mammary tissue slices. Journal of Nutrition 142(3):484-491. [3]Ban, H., K. Shigemitsu, T. Yamatsuji, et al. 2004. Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells. International Journal of Molecular Medicine 13(4):537-543. [4]Bhaskar, P.T. and N. Hay. 2007. The two TORCs and Akt. Developmental Cell 12(4):487. [5]Bianchi, G., R. Marzocchi, F. Agostini, et al. 2005. Update on nutritional supplementation with branched-chain amino acids. Current Opinion in Clinical Nutrition & Metabolic Care 8(1):83-87. [6]Cheng, Y., Q. S. Meng, C. X. Wang, et al. 2010. Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue. Diabetes 59(1):17-25. [7]Chotechuang, N., D. Azzoutmarniche, C. Bos, et al. 2009. mTOR, AMPK, and GCN2 coordinate the adaptation of hepatic energy metabolic pathways in response to protein intake in the rat. American Journal of Physiology Endocrinology & Metabolism 297(6):E1313. [8]Cota, D., K. Proulx, K. A. B. Smith, et al. 2006. Hypothalamic mTOR Signaling Regulates Food Intake. Science 312(5775):927-930. [9]Crozier, S.J., M. D. Sans, L. Guo, et al. 2006. Activation of the mTOR signalling pathway is required for pancreatic growth in protease-inhibitor-fed mice. J Physiol 573(3):775-786. [10]Deval, C., C. Chaveroux, A. C. Maurin, et al. 2009. Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways. Febs Journal 276(3):707. [11]Doi, M., I. Yamaoka, T. Fukunaga, et al. 2003. Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. Biochemical & Biophysical Research Communications 312(4):1111-1117. [12]Dong, J., H. Qiu, M. Garcia-Barrio, et al. 2000. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Molecular Cell 6(2):269-279. [13]Dreyer, H.C., M. J. Drummond, B. Pennings, et al. 2008. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. American Journal of Physiology Endocrinology & Metabolism 294(1):392-400. [14]Drummond, M.J., J. A. Bell, S. Fujita, et al. 2008. Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle. Clinical Nutrition 27(3):447-456. [15]Du, Y., Q. Meng, Q. Zhang, et al. 2012. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids 43(2):725. [16]Dunshea, F.R., D. E. Bauman, E. A. Nugent, et al. 2005. Hyperinsulinaemia, supplemental protein and branched-chain amino acids when combined can increase milk protein yield in lactating sows. British Journal of Nutrition 93(3):325-332. [17]Escobar, J., J. W. Frank, A. Suryawan, et al. 2005. A physiological rise in leucine, but not isoleucine or valine, increases protein synthesis and translation initiation factor activation in skeletal muscle of neonatal pigs. Pages A976-A976 in Proc. Experimental Biology 2005 Meeting/ International Congress of. [18]Fingar, D.C., S. Salama, C. Tsou, et al. 2002. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes & Development 16(12):1472-1487. [19]Gallinetti, J., E. Harputlugil, and J. R. Mitchell. 2013. Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochemical Journal 449(1):1-10. [20]Gao, H.N., H. Hu, N. Zheng, et al. 2015. Leucine and histidine independently regulate milk protein synthesis in bovine mammary epithelial cells via mTOR signaling pathway. Journal of Zhejiang Universityence B 16(6):560-572. [21]Gordon-Elliott, J.S. and H. C. Margolese. 2006. Weight loss during prolonged branched-chain amino acid treatment for tardive dyskinesia in a patient with schizophrenia. Australian & New Zealand Journal of Psychiatry 40(2):195-195. [22]Guo, F.and D. R. Cavener. 2007. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metabolism 5(2):103-114. [23]Hao, S., J. W. Sharp, C. M. Ross-Inta, et al. 2005. Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307(5716):1776-1778. [24]Harding, H.P., Y. Zhang, H. Zeng, et al. 2003. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular Cell 11(3):619. [25]Hashimoto, N.and H. Hara. 2003. Dietary amino acids promote pancreatic protease synthesis at the translation stage in rats. Journal of Nutrition 133(10):3052. [26]Hinnebusch, A.G. 1994. The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress. Seminars in Cell Biology 5(6):417. [27]Iwanaka, N., T. Egawa, N. Satoubu, et al. 2010. Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle. Journal of Applied Physiology 108(2):274-282. [28]Jin, H.O., S. K. Seo, S. H. Woo, et al. 2009. SP600125 negatively regulates the mammalian target of rapamycin via ATF4-induced Redd1 expression. Febs Letters 583(1):123-127. [29]Jr, J.D., R. G. Pedrosa, V. F. Cruzat, et al. 2006. Effects of leucine supplementation on the body composition and protein status of rats submitted to food restriction. Nutrition 22(5):520-527. [30]Julien, A., L. L. Sarah, M. Florent, et al. 2016. GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism. Sci Rep 6:27698. [31]Kilberg, M.S., Y. X. Pan, H. Chen, et al. 2005. Nutritional Control of Gene Expression: How Mammalian Cells Respond to Amino Acid Limitation. Annual Review of Nutrition 25(1):59. [32]Kilberg, M.S., J. Shan, and N. Su. 2009. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends in Endocrinology & Metabolism Tem 20(9):436. [33]Kim, S.W., D. R. Mateo, Y. Yin, et al. 2007. Functional Amino Acids and Fatty Acids for Enhancing Production Performance of Sows and Piglets. Asian-Australasian Journal of Animal Sciences 20(2):295-306. [34]Kimball, S.R., A. N. Do, L. Kutzler, et al. 2008. Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis. Journal of Biological Chemistry 283(6):3465. [35]Kimball, S.R. and L. S. Jefferson. 2002. Control of protein synthesis by amino acid availability. Current Opinion in Clinical Nutrition & Metabolic Care 5(1):63-67. [36]Kimball, S.R. and L. S. Jefferson. 2004. Regulation of global and specific mRNA translation by oral administration of branched-chain amino acids. Biochemical & Biophysical Research Communications 313(2):423-427. [37]Kimball, S.R. and L. S. Jefferson. 2006. New functions for amino acid: effects on gene transcription and translation. American Journal of Clinical Nutrition 83:S500-507. [38]Kong, Y.C., W. R. Moyle, and J. Ramachandran. 2014. A Metabolic Enzyme, Pyruvate Dehydrogenase Kinase 4, Regulates mTOR, a Key Cell Signaling Kinase? PDK4 Protein Promotes Tumorigenesis through Activation of cAMP-response Element-binding Protein (CREB)-Ras Homolog Enriched in Brain (RHEB)-mTORC1 Signaling. Journal of Biological Chemistry 289(1):350-352. [39]Kubota, H., K. Ota, Y. Sakaki, et al. 2001. Budding yeast GCN1 binds the GI domain to activate the eIF2alpha kinase GCN2. Journal of Biological Chemistry 276(20):17591. [40]Laufenberg, L.J., A. M. Pruznak, M. Navaratnarajah, et al. 2014. Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle. Amino Acids 46(12):2787-2798. [41]Layman, D.K. and D. A. Walker. 2006. Potential importance of leucine in treatment of obesity and the metabolic syndrome. Journal of Nutrition 136(1 Suppl):319S. [42]Liu, L., L. Chen, J. Chung, et al. 2008. Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene 27(37):4998-5010. [43]Lynch, C.J., B. Gern, C. Lloyd, et al. 2006. Leucine in food mediates some of the postprandial rise in plasma leptin concentrations. American Journal of Physiology Endocrinology & Metabolism 291(3):E621. [44]Lynch, C.J., B. J. Patson, J. Anthony, et al. 2002. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab 283(3):E503. [45]Ma, X.and J. Blenis. 2009. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307-318. [46]Moser, S.A., M. D. Tokach, S. S. Dritz, et al. 2000. The effects of branched-chain amino acids on sow and litter performance. Journal of animal science 78(3):658-667. [47]Moshel, Y., R. E. Rhoads, and I. Barash. 2006. Role of amino acids in translational mechanisms governing milk protein synthesis in murine and ruminant mammary epithelial cells. J Cell Biochem 98(3):685. [48]Narasimhan, J., K. A. Staschke, and R. C. Wek. 2004. Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions. Journal of Biological Chemistry 279(22):22820-22832. [49]Nicklin, P.2009. Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy. Cell 136(3):521-534. [50]Sans, M.D., M. Tashiro, N. L. Vogel, et al. 2006. Leucine activates pancreatic translational machinery in rats and mice through mTOR independently of CCK and insulin. Journal of Nutrition 136(7):1792. [51]Schmelzle, T.and M. N. Hall. 2000. TOR, a central controller of cell growth. Cell 103(2):253. [52]Talvas, J., A. Obled, P. Fafournoux, et al. 2006. Regulation of protein synthesis by leucine starvation involves distinct mechanisms in mouse C2C12 myoblasts and myotubes. Journal of Nutrition 136(6):1466-1471. [53]Wang, Y., J. Liu, H. Wu, et al. 2016. Amino acids regulate mTOR pathway and milk protein synthesis in a mouse mammary epithelial cell line is partly mediated by T1R1/T1R3. European Journal of Nutrition:1-8. [54]Wu, G.Y. 2009. Amino acids: metabolism, functions, and nutrition. Amino Acids 37(1):1-17. [55]Xiao, F., Z. Huang, H. Li, et al. 2011. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes 60(3):746-756. [56]Xu, G., G. Kwon, C. A. Marshall, et al. 1998. Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells. A possible role in protein translation and mitogenic signaling. Journal of Biological Chemistry 273(43):28178. [57]Yang, J., Y. Chi, B. R. Burkhardt, et al. 2010. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr Rev 68(5):270–279. [58]Ye, J., W. Palm, M. Peng, et al. 2015. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes & Development 29(22):2331-2336. [59]Yin, Y., K. Yao, Z. Liu, et al. 2010. Supplementing L-leucine to a low-protein diet increases tissue protein synthesis in weanling pigs. Amino Acids 39(5):1477-1486. [60]Yoshizawa, F.2004. Regulation of protein synthesis by branched-chain amino acids in vivo. Biochemical & Biophysical Research Communications 313(2):417-422. [61]Zhang, P., B. C. Mcgrath, J. Reinert, et al. 2002a. The GCN2 eIF2α Kinase Is Required for Adaptation to Amino Acid Deprivation in Mice. Molecular & Cellular Biology 22(19):6681-6688. [62]Zhang, P., B. C. Mcgrath, J. Reinert, et al. 2002b. The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Molecular & Cellular Biology 22(19):6681-6688. [63]Zhang, Y., K. Guo, R. E. Leblanc, et al. 2007. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56(6):1647-1654. [64]陈熠, 彭艺, 贺建华, et al.2009. 日粮中添加缬氨酸对泌乳母猪生产性能及其仔猪生长性能的影响. 动物营养学报 21(5):727-733. [65]Chen Y., Peng Y., He J. H., et al. 2009. Effects of dietary valine supplementation on productive performance of lactating sows and growth performance of suckling piglets. Chinese Journal of Animal Nutrition 21:727-733. [66]李方方, 王军, 林燕, et al.2013. 饲粮缬氨酸与赖氨酸比对初产母猪繁殖性能及血清生化指标的影响. 动物营养学报 25(4):720-728. [67]Li F.F., Wang J., Lin Y., et al. 2013. Effects of dietary valine/lysine on reproductive performance and serum biochemical indices of gilts. Chinese Journal of Animal Nutrition 25:720-728. [68]M, H.K. and C. D. P. 2016. 瘤胃可降解缬氨酸对泌乳后期奶牛产奶量的影响. 饲料博览 (3). [69]M, H.K. and C. D. P. 2016. Rumen degradable valine effects on the milk production of cows in late lactation. Feed Review (3).
