综述 Review

α-酮戊二酸的生理功能及其在动物生产中的应用

展开
  • 1. 湖南农业大学动物科学技术学院, 长沙 410128;
    2. 中国科学院亚热带农业生态研究所, 亚热带农业生态过程重点实验室, 湖南省畜禽健康养殖工程技术中心, 长沙 410125;
    3. 衡阳师范学院生命科学与环境学院, 衡阳 421002;
    4. 湖南农业大学, 湖南省植物功能成分利用协同创新中心, 长沙 410128
陈家顺(1988-),男,安徽亳州人,博士研究生,从事动物营养生理代谢与调控研究。E-mail:730273902@qq.com

收稿日期: 2018-03-29

  网络出版日期: 2018-10-20

基金资助

国家自然科学基金青年科学基金项目(31702126);湖南省研究生科研创新项目(CX2017B348);湖南省教育厅科学研究项目优秀青年项目(17B121);湖南农业大学省级优秀博士学位论文培育基金项目(YB2017002);湖南省"湖湘青年科技创新人才"项目(2015RS4053);中科院"百人计划"项目

Physiological Function of Alpha-Ketoglutarate and Its Application in Animal Production

Expand
  • 1. College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China;
    2. Hunan Provincial Engineering Research Center for Healthy Breeding of Livestock and Poultry, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China;
    3. College of Life Science and Environment, Hengyang Normal University, Hengyang 421002, China;
    4. Hunan Collaborative Innovation Center for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha 410128, China

Received date: 2018-03-29

  Online published: 2018-10-20

摘要

α-酮戊二酸(AKG)是三羧酸循环中的中心物质,也是氨基酸和碳水化合物代谢的桥梁。AKG作为铵离子清除剂,是提供谷氨酰胺的来源,能够促进肌肉蛋白质合成和抑制蛋白质降解,并为胃肠道细胞提供能量代谢的燃料。AKG可以通过脯氨酰-4-羟化酶产生脯氨酸,增加胶原蛋白合成,促进骨骼系统发育。此外,AKG可以抑制ATP合成酶和雷帕霉素靶蛋白,延长线虫的寿命。AKG不仅延长寿命,而且延迟与年龄相关的疾病。另外,AKG在消除毒性、提高耐寒性、缓解氧化应激损伤以及促进人类多潜能干细胞分化等方面具有关键作用。本文旨在对AKG的生理功能及其在动物生产领域的应用进行综述,以促进人们对AKG的理解,为AKG在动物营养调控和生产实践中的应用提供理论依据。

本文引用格式

陈家顺, 苏文璇, 符晨星, 姚康 . α-酮戊二酸的生理功能及其在动物生产中的应用[J]. 动物营养学报, 2018 , 30(10) : 3818 -3827 . DOI: 10.3969/j.issn.1006-267x.2018.10.004

Abstract

Alpha-ketoglutarate (AKG) is the central substance in the tricarboxylic acid cycle and it is also a bridge for amino acid and carbohydrate metabolism. As an ammonium ion scavenger, AKG is a source of glutamine that promotes muscle protein synthesis, inhibits protein degradation, and provides fuel for energy metabolism in gastrointestinal cells. AKG can produce proline via prolyl-4-hydroxylase, increase collagen synthesis, and promote the development of the skeletal system. In addition, AKG can inhibit ATP synthase and mammalian target of rapamycin to extend the longevity of C. elegans, which not only prolongs lifespan, but also delays age-related diseases. Besides, AKG plays a key role in eliminating toxicity, improving cold resistance, alleviating oxidative stress damage, and promoting the differentiation of human pluripotent stem cells. The objective of this article is to review the physiological functions of AKG and its application in animal production, which promotes people's understanding of AKG, providing theoretical basis for the application of AKG in animal nutrition regulation and production practice, and calling for more research focus on AKG.

参考文献

[1] CHIN R M,FU X D,PAI M Y,et al.The metabolite alpha-ketoglutarate extends lifespan by inhibiting the ATP synthase and TOR[J].Nature,2014,510(7505):397-401.  

[2] DAKEK M,KRUSZEWSKA D,FILIP R,et al.α-ketoglutarate (AKG) absorption from pig intestine and plasma pharmacokinetics[J].Journal of Animal Physiology and Animal Nutrition,2005,89(11/12):419-426.

[3] JUNGHANS P,DERNO M,PIERZYNOWSKI S,et al.Intraduodenal infusion of α-ketoglutarate decreases whole body energy expenditure in growing pigs[J].Clinical Nutrition,2006,25(3):489-496.  

[4] LAMBERT B D,FILIP R,STOLL B,et al.First-pass metabolism limits the intestinal absorption of enteral α-ketoglutarate in young pigs[J].Journal of Nutrition,2006,136(11):2779-2784.  

[5] CYNOBER L.Ornithine α-ketoglutarate as a potent precursor of arginine and nitric oxide:a new job for an old friend[J].The Journal of Nutrition,2004,134(10):2858S-2862S.

[6] SON E D,CHOI G H,KIM H,et al.Alpha-ketoglutarate stimulates procollagen production in cultured human dermal fibroblasts,and decreases UVB-induced wrinkle formation following topical application on the dorsal skin of hairless mice[J].Biological and Pharmaceutical Bulletin,2007,30(8):1395-1399.  

[7] HARRISON A P,PIERZYNOWSKI S G.Biological effects of 2-oxoglutarate with particular emphasis on the regulation of protein,mineral and lipid absorption/metabolism,muscle performance,kidney function,bone formation and cancerogenesis,all viewed from a healthy ageing perspective state of the art-review article[J].Journal of Physiology and Pharmacology,2008,59(Suppl.1):91-106.

[8] RIEDEL E,NVNDEL M,HAMPL H.α-ketoglutarate application in hemodialysis patients improves amino acid metabolism[J].Nephron,1996,74(2):261-265.  

[9] JONES C,PALMER T E A,GRIFFITHS R.Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition[J].Nutrition,1999,15(2):108-115.  

[10] STOLL B,MCNELLY S,BUSCHER H P,et al.Functional hepatocyte heterogeneity in glutamate,aspartate and α-ketoglutarate uptake:a histoautoradiographical study[J].Hepatology,1991,13(2):247-253.  

[11] KRISTENSEN N B,JUNGVID H,FERNANDEZ J A,et al.Absorption and metabolism of α-ketoglutarate in growing pigs[J].Journal of Animal Physiology and Animal Nutrition,2002,86(7/8):239-245.

[12] ?LIWA E,DOBROWOLSKI P,TATARA M R,et al.Alpha-ketoglutarate protects the liver of piglets exposed during prenatal life to chronic excess of dexamethasone from metabolic and structural changes[J].Journal of Animal Physiology and Animal Nutrition,2009,93(2):192-202.  

[13] TOCAJ A,FILIP R,LINDERGARD B,et al.α-ketoglutarate (AKG) inhibit osteoporosis development in postmenopausal women[J].Journal of Bone and Mineral Research,2003,18:S267-S267.

[14] YAO K,YIN Y L,LI X L,et al.Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells[J].Amino Acids,2012,42(6):2491-2500.  

[15] LAMANDE S R,BATEMAN J F.Procollagen folding and assembly:the role of endoplasmic reticulum enzymes and molecular chaperones[J].Seminars in Cell & Developmental Biology,1999,10(5):455-464.  

[16] WU G Y,FANG Y Z,YANG S,et al.Glutathione metabolism and its implications for health[J].The Journal of Nutrition,2004,134(3):489-492.  

[17] KORKMAZ A,YURDAKÖK M,YIGIT S,et al.Long-term enteral glutamine supplementation in very low birth weight infants:effects on growth parameters[J].Turkish Journal of Pediatrics,2007,49(1):37-44.

[18] KARNA E,SZOKA L,PALKA J A.The mechanism of hydralazine-induced collagen biosynthesis in cultured fibroblasts[J].Naunyn-Schmiedeberg's Archives of Pharmacology,2013,386(4):303-309.  

[19] BELLON G,CHAQOUR B,WEGROWSKI Y,et al.Glutamine increases collagen gene transcription in cultured human fibroblasts[J].Biochimica et Biophysica Acta:Molecular Cell Research,1995,1268(3):311-323.  

[20] HARRISON A P,TYGESEN M P,SAWA-WOJTANOWICZ B,et al.α-ketoglutarate treatment early in postnatal life improves bone density in lambs at slaughter[J].Bone,2004,35(1):204-209.  

[21] FAYH A P,FRIEDMAN R,SAPATA K B,et al.Effect of L-arginine supplementation on secretion of human growth hormone and insuline-like growth factor in adults[J].Arquivos Brasileiros de Endocrinologia and Metabologia,2007,51(4):587-592.  

[22] GIUSTINA A,MAZZIOTTI G,CANALIS E.Growth hormone,insulin-like growth factors,and the skeleton[J].Endocrine Reviews,2008,29(5):535-559.  

[23] GU Y,GENEVER P G,SKERRY T M,et al.The NMDA type glutamate receptors expressed by primary rat osteoblasts have the same electrophysiological characteristics as neuronal receptors[J].Calcified Tissue International,2002,70(3):194-203.  

[24] MENTAVERRI R,KAMEL S,WATTEL A,et al.Regulation of bone resorption and osteoclast survival by nitric oxide:possible involvement of NMDA-receptor[J].Journal of Cellular Biochemistry,2003,88(6):1145-1156.  

[25] SPENCER G J,MCGRATH C J,GENEVER P G.Current perspectives on NMDA-type glutamate signaling in bone[J].The International Journal of Biochemistry & Cell Biology,2007,39(6):1089-1104.  

[26] RADZKI R P,BIENKO M,PIERZYNOWSKI S G.Anti-osteopenic effect of alpha-ketoglutarate sodium salt in ovariectomized rats[J].Journal of Bone and Mineral Metabolism,2012,30(6):651-659.  

[27] DOBROWOLSKI P J,PIERSIAK T,SURVE V V,et al.Dietary α-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats[J].Scandinavian Journal of Gastroenterology,2008,43(5):551-558.  

[28] ZIEGLER T R,DAIGNAULT N M.Glutamine regulation of human immune cell function[J].Nutrition,2000,16(6):458-459.  

[29] 夏利宁,陶刚,王凤英,等.改进型中草药921合剂结合α-酮戊二酸对断奶大鼠肠道免疫的影响[J].新疆农业大学学报,2004,27(2):91-95.

[30] 王蕾,吴信,付大波.α-酮戊二酸对动物肠道黏膜作用的研究进展[J].黑龙江畜牧兽医,2010(11):36-37.

[31] TAPIERO H,MATHAÉ G,COUVREUR P,et al.Ⅱ.Glutamine and glutamate[J].Biomedicine & Pharmacotherapy,2002,56(9):446-457.  

[32] ZIMMERMAN J J,RINGER T V.Inflammatory host responses in sepsis[J].Critical Care Clinics,1992,8(1):163-189.  

[33] OGLE C K,OGLE J D,MAO J X,et al.Effect of glutamine on phagocytosis and bacterial killing by normal and pediatric burn patient neutrophils[J].Journal of Parenteral and Enteral Nutrition,1994,18(2):128-133.  

[34] FURUKAWA S,SAITO H,INOUE T,et al.Supplemental glutamine augments phagocytosis and reactive oxygen intermediate production by neutrophils and monocytes from postoperative patients in vitro[J].Nutrition,2000,16(5):323-329.  

[35] BOYER P D.The ATP synthase-a splendid molecular machine[J].Annual Review of Biochemistry,1997,66:717-749.

[36] LOMENICK B,HAO R,JONAI N,et al.Target identification using drug affinity responsive target stability (DARTS)[J].Proceedings of the National Academy of Sciences of the United States of America,2009,106(51):21984-21989.  

[37] TSANG W Y,SAYLES L C,GRAD L I,et al.Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span[J].Journal of Biological Chemistry,2001,276(34):32240-32246.  

[38] LEE S S,LEE R Y,FRASER A G,et al.A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity[J].Nature Genetics,2003,33(1):40-48.  

[39] KAEBERLEIN M,BURTNER C R,KENNEDY B K.Recent developments in yeast aging[J].PLoS Genetics,2007,3(5):e84.

[40] VELLAI T,TAKACS-VELLAI K,ZHANG Y,et al.Genetics:influence of TOR kinase on lifespan in C. elegans[J].Nature,2003,426(6967):620.

[41] KAPAHI P,ZID B.TOR pathway:linking nutrient sensing to life span[J].Science of Aging Knowledge Environment,2004,2004(36):PE34.

[42] SELMAN C,TULLET J M A,WIESER D,et al.Ribosomal protein S6 kinase 1 signaling regulates mammalian life Span[J].Science,2009,326(5949):140-144.  

[43] URBAN J,SOULARD A,HUBER A,et al.Sch9 is a major target of TORC1 in Saccharomyces cerevisiae[J].Molecular Cell,2007,26(5):663-674.  

[44] HARDIE D G,ROSS F A,HAWLEY S A.AMPK:a nutrient and energy sensor that maintains energy homeostasis[J].Nature Reviews Molecular Cell Biology,2012,13(4):251-262.  

[45] TOIVONEN J M,WALKER G A,MARTINEZ-DIAZ P,et al.No influence of Indy on lifespan in Drosophila after correction for genetic and cytoplasmic background effects[J].PLoS Genetics,2007,3(6):e95.

[46] GROSS D N,WAN M,BIRNBAUM M J.The role of FoxO in the regulation of metabolism[J].Current Diabetes Reports,2009,9(3):208-214.  

[47] WANG Y,ZHOU Y M,GRAVES D T.FOXO transcription factors:their clinical significance and regulation[J].Biomed Research International,2014,2014:925350.

[48] WEBB A E,BRUNET A.FOXO transcription factors:key regulators of cellular quality control[J].Trends in Biochemical Sciences,2014,39(4):159-169.  

[49] SHEAFFER K L,UPDIKE D L,MANGO S E.The target of rapamycin pathway antagonizes pha-4/FoxA to control development and aging[J].Current Biology,2008,18(18):1355-1364.  

[50] WULLSCHLEGER S,LOEWITH R,HALL M N.TOR signaling in growth and metabolism[J].Cell,2006,124(3):471-484.  

[51] STANFEL M N,SHAMIEH L S,KAEBERLEIN M,et al.The TOR pathway comes of age[J].Biochimica et Biophysica Acta:General Subjects,2009,1790(10):1067-1074.  

[52] MELÉNDEZ A,TALLOCZY Z,SEAMAN M,et al.Autophagy genes are essential for dauer development and life-span extension in C. elegans[J].Science,2003,301(5638):1387-1391.  

[53] BRAUER M J,YUAN J,BENNETT B D,et al.Conservation of the metabolomic response to starvation across two divergent microbes[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103(51):19302-19307.  

[54] KAMINSKY Y G,KOSENKO E A,KONDRASHOVA M N.Metabolites of citric acid cycle,carbohydrate and phosphorus metabolism,and related reactions,redox and phosphorylating states of hepatic tissue,liver mitochondria and cytosol of the pigeon,under normal feeding and natural nocturnal fasting conditions[J].Comparative Biochemistry and Physiology Part B:Comparative Biochemistry,1982,73(4):957-963.  

[55] BRUGNARA L,VINAIXA M,MURILLO S,et al.Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus[J].PLoS One,2012,7(7):e40600.

[56] BHATTACHARYA R,RAO P,SINGH P,et al.Biochemical,oxidative and histological changes caused by sub-acute oral exposure of some synthetic cyanogens in rats:ameliorative effect of α-ketoglutarate[J].Food and Chemical Toxicology,2014,67:201-211.

[57] BAYLIAK M M,LYLYK M P,SHMIHEL H V,et al.Dietary alpha-ketoglutarate increases cold tolerance in Drosophila melanogaster and enhances protein pool and antioxidant defense in sex-specific manner[J].Journal of Thermal Biology,2016,60:1-11.

[58] YANG Q Y,LIANG X W,SUN X F,et al.AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis[J].Cell Metabolism,2016,24(4):542-554.  

[59] REINOSO C A,AUGER C,APPANNA V D,et al.Tellurite-exposed Escherichia coli exhibits increased intracellular α-ketoglutarate[J].Biochemical and Biophysical Research Communications,2012,421(4):721-726.  

[60] TESLAA T,CHAIKOVSKY A C,LIPCHINA I,et al.α-ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells[J].Cell Metabolism,2016,24(3):485-493.  

[61] HWANG I Y,KWAK S,LEE S,et al.Psat1-dependent fluctuations in α-ketoglutarate affect the timing of ESC differentiation[J].Cell Metabolism,2016,24(3):494-501.  

[62] JEEVANANDAM M,ALI M R,RAMIAS L,et al.Efficacy of ornithine-alpha-ketoglutarate (OKGA) as a dietary supplement in growing rats[J].Clinical Nutrition,1991,10(3):155-161.  

[63] PIVA A,MORLACCHINI M,PRANDINI A,et al.Ketoglutaric acid reduces nitrogen losses in rats fed nitrogen-free diet[J].Digestive Physiology of Pigs,2001,24:101-103.

[64] PRANDINI A,MORLACCHINI M,SIGOLO S,et al.Anticatabolic activity of alpha-ketoglutaric acid in growing rats[J].Italian Journal of Animal Science,2012,11(3):e52.

[65] CHEN J S,WU F,YANG H S,et al.Growth performance,nitrogen balance,and metabolism of calcium and phosphorus in growing pigs fed diets supplemented with alpha-ketoglutarate[J].Animal Feed Science and Technology,2017,226:21-28.

[66] WANG L S,XU Q Y,WANG C A,et al.Effects of dietary α-ketoglutarate supplementation on the growth performance,glutamine synthesis and amino acid concentrations of juvenile hybrid sturgeon Acipenser schrenckii♀×A. baerii fed high levels of soy protein concentrate[J].Animal Feed Science and Technology,2015,211:199-207.

[67] 位莹莹,徐奇友,李晋南,等.不同蛋白质水平饲料中添加α-酮戊二酸对松浦镜鲤生长性能、体成分和血清生化指标的影响[J].动物营养学报,2013,25(12):2958-2965.

[68] KOWALIK S,WAWRZYNIAK-GACEK A,PIERSIAK T,et al.Relation between growth and bone collagen content in young pigs; effects of dietary α-ketoglutarate supplementation[J].Bulletin-Veterinary Institute in Pulawy,2011,55(2):287-292.

[69] BLOMQVIST B I,HAMMARQVIST F,VON DER DECKEN A,et al.Glutamine and α-ketoglutarate prevent the decrease in muscle free glutamine concentration and influence protein synthesis after total hip replacement[J].Metabolism,1995,44(9):1215-1222.  

[70] TATARA M R,TYGESEN M P,SAWA-WOJTANOWICZ B,et al.Bone development:the effect of short-term alpha-ketoglutarate administration on long-term mechanical properties of ribs in ram lambs[J].Small Ruminant Research,2007,67(2/3):179-183.

[71] KOWALIK S,SLIWA E,TATARA M R,et al.Influence of alpha-ketoglutarate on mineral density and geometrical and mechanical parameters of femora during postnatal life in piglets[J].Bulletin-Veterinary Institute in Pulawy,2005,49(1):107-111.

[72] ANDERSEN N K,TATARA M R,KRUPSKI W,et al.The long-term effect of α-ketoglutarate,given early in postnatal life,on both growth and various bone parameters in pigs[J].Journal of Animal Physiology and Animal Nutrition,2008,92(5):519-528.  

[73] TATARA M R,KRUPSKI W,TYMCZYNA B,et al.Effects of combined maternal administration with alpha-ketoglutarate (AKG) and β-hydroxy-β-methylbutyrate (HMB) on prenatal programming of skeletal properties in the offspring[J].Nutrition & Metabolism,2012,9:39.

[74] TATARA M R,PIERZYNOWSKI S G,MAJCHER P,et al.Effect of alpha-ketoglutarate (AKG) on mineralisation,morphology and mechanical endurance of femur and tibia in Turkey[J].Bulletin-Veterinary Institute in Pulawy,2004,48(3):305-309.

[75] TATARA M R,BRODZKI A,KRUPSKI W,et al.Effects of alpha-ketoglutarate on bone homeostasis and plasma amino acids in turkeys[J].Poultry Science,2005,84(10):1604-1609.  

[76] SCHLEGEL L,COUDRAY-LUCAS C,BARBUT F,et al.Bacterial dissemination and metabolic changes in rats induced by endotoxemia following intestinal E. coli overgrowth are reduced by ornithine α-ketoglutarate administration[J].The Journal of Nutrition,2000,130(12):2897-2902.  

[77] HOU Y Q,WANG L,DING B Y,et al.Dietary α-ketoglutarate supplementation ameliorates intestinal injury in lipopolysaccharide-challenged piglets[J].Amino Acids,2010,39(2):555-564.  

[78] 胡泉舟.α-酮戊二酸对断奶仔猪生长性能和肠道功能的影响[D].硕士学位论文.武汉:武汉工业学院,2008.

[79] 王金泉,项方献,姚刚.中草药结合AKG对断奶仔猪生长及消化吸收功能的影响[J].西北农林科技大学学报(自然科学版),2011,39(5):27-31.

[80] 刘少娟,陈家顺,康保聚,等.α-酮戊二酸和大蒜素对生长猪生长发育及养分表观消化率的影响[J].动物营养学报,2017,29(9):3193-3201.

[81] CHEN J H,YANG H H,LONG L N,et al.The effects of dietary supplementation with α-ketoglutarate on the intestinal microbiota,metabolic profiles,and ammonia levels in growing pigs[J].Animal Feed Science and Technology,2017,234:321-328.

[82] 余亲平,陈雁群,谢金蝉,等.日粮添加α-酮戊二酸对肉仔鸡生长性能及组织器官发育的影响[J].中国畜牧兽医,2010,37(10):10-14.

[83] 晏利琼,廖满,谢佳倩,等.L-精氨酸和α-酮戊二酸对热应激肉鸡肠道吸收功能、抗氧化能力、能量代谢的影响[J].中国畜牧杂志,2016,52(15):33-41.

[84] INOKI K,GUAN K L.Complexity of the TOR signaling network[J].Trends in Cell Biology,2006,16(4):206-212.  

[85] KATEWA S D,KAPAHI P.Role of TOR signaling in aging and related biological processes in Drosophila melanogaster[J].Experimental Gerontology,2011,46(5):382-390.  

[86] BLAGOSKLONNY M V.Aging and immortality:quasi-programmed senescence and its pharmacologic inhibition[J].Cell Cycle,2006,5(18):2087-2102.  
文章导航

/