豬氨基酸代謝節(jié)儉機制新假說

孫志洪 李 貌 許慶慶 印遇龍 朱偉云 江青艷 黃飛若

(1. 西南大學生物飼料與分子營養(yǎng)實驗室，重慶400715；2.中國科學院亞熱帶農業(yè)生態(tài)研究所，長沙410125；3.南京農業(yè)大學動物科技學院，南京210095；4.華南農業(yè)大學動物科技學院，廣州510642；5.華中農業(yè)大學動物科技學院，武漢430070)

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豬氨基酸代謝節(jié)儉機制新假說

孫志洪1李 貌1許慶慶1印遇龍2朱偉云3江青艷4黃飛若5

(1. 西南大學生物飼料與分子營養(yǎng)實驗室，重慶400715；2.中國科學院亞熱帶農業(yè)生態(tài)研究所，長沙410125；3.南京農業(yè)大學動物科技學院，南京210095；4.華南農業(yè)大學動物科技學院，廣州510642；5.華中農業(yè)大學動物科技學院，武漢430070)

豬尿氮排放量為總氮排放量的60%～70%，而尿素是尿液中的主要含氮物，其合成速率在很大程度上決定著尿氮以及總氮的排放量。因此，降低豬肝臟尿素合成速率是減少氮排放量的根本途徑。本文首先介紹了當前豬氮減排常用的營養(yǎng)調控技術，然后分別就肝臟尿素合成的直接前體物(氨)與間接前體物(如甘氨酸和丙氨酸)以及氨基酸代謝燃料功能替代機制進行論述，在此基礎上提出豬氨基酸代謝節(jié)儉機制新假說，即促進丙酮酸/葡萄糖等物質的供能效率，以降低谷氨酸等氨基酸的代謝速率，從而達到減少門靜脈尿素前體物凈流量、肝臟尿素合成以及尿氮排放量的目的。

豬；氮排放；氨基酸；代謝節(jié)儉；丙酮酸脫氫酶

近年來，氮排放引發(fā)的環(huán)境污染隨畜禽養(yǎng)殖規(guī)模和集約化程度的不斷擴大而日趨嚴重。目前，全球畜禽氮排放量的估計值高達8 900萬～16 400萬t；我國畜禽氮排放量約為3 000萬t，其中單胃動物(主要是豬)的氮排放量約占總氮排放量的60%。與此同時，蛋白質資源緊缺是全世界共同面臨的問題；2014年，中國蛋白質飼料原料的進口量約為4 000萬t，魚粉和大豆的進口依存度達到70%。因此，如何提高蛋白質的利用效率、減少氮排放量已成為我國畜禽養(yǎng)殖業(yè)尤其是養(yǎng)豬業(yè)迫切需要解決的科學問題。

1 豬氮減排常用的營養(yǎng)調控技術

目前圍繞生豬氮排放已經開展了大量研究，包括以理想氨基酸模式為基礎配制飼糧[1]、降低飼糧蛋白質含量并補充限制性氨基酸[2-7]、增加飼糧中可發(fā)酵性碳水化合物的比例[2,8-9]以及添加酶制劑、益生素和有機酸等添加劑[10-11]。盡管大量研究已經證實低蛋白質飼料可顯著降低豬的氮排放量[2,6,12-13]，但這一營養(yǎng)調控措施尚未成為養(yǎng)豬生產業(yè)的通用技術，尤其是在以獲取快速生長為目標的集約化生產體系中；其他營養(yǎng)調控技術也只能在一定程度上減少豬的氮排放量。

鑒此，有必要深入研究豬的氮排放機制以明確關鍵調控靶點。豬尿氮排放量占總氮排放量的比例為60%～70%[9,14-15]，而尿素是尿液中的主要含氮物，其合成速率在很大程度上決定了尿氮以及總氮的排放量。因此，降低豬肝臟尿素合成速率是減少氮排放量的重要策略，而明確尿素前體物的種類與來源則是開展氮減排研究的首要前提。

2 尿素前體物

2.1 氨——尿素的直接前體物

氨為尿素的直接前體物，主要來源于氨基酸的分解代謝。門靜脈回流組織(portal-drained viscera，PDV)是氨基酸代謝的重要場所，如飼糧中97%的谷氨酸和天門冬氨酸、70%的谷氨酰胺、40%～50%的絲氨酸和甘氨酸、40%的精氨酸和脯氨酸、20%～40%的支鏈氨基酸以及30%～60%的其他必需氨基酸均在PDV中發(fā)生分解代謝[4,16-20]。氨基酸脫氨后轉化為乙酰輔酶A、丙酮酸、草酰乙酸、琥珀酰輔酶A、延胡索酸和α-酮戊二酸等物質進入三羧酸(tricarboxylic acid，TCA)循環(huán)以氧化供能[21](圖1)。氨基酸在PDV中的廣泛代謝導致門靜脈血氨濃度遠高于其他部位，進入肝臟后大部分血氨用于尿素的合成[22]。

Glucose：葡萄糖；pyruvate：丙酮酸；threonine：蘇氨酸；cysteine：半胱氨酸；serine：絲氨酸；glycine：甘氨酸；alanine：丙氨酸；tryptophan：色氨酸；lysine：賴氨酸；leucine：亮氨酸；isoleucine：異亮氨酸；tyrosine：酪氨酸；phenylalanine：苯丙氨酸；acetyl-CoA：乙酰輔酶A；citrate：檸檬酸；isocitrate：異檸檬酸；glutamine：谷氨酰胺；histidine：組氨酸；arginine：精氨酸；proline：脯氨酸；glutamate：谷氨酸；α-ketoglutarate：α-酮戊二酸；succinyl-CoA：琥珀酰輔酶A；methionine：蛋氨酸；valine：纈氨酸；succinate：琥珀酸；fumarate：富馬酸；malate：蘋果酸；oxaloacetate：草酰乙酸；aspartate：天門冬氨酸；NAD+：煙酰胺腺嘌呤二核苷酸nicotinamide adenine dinucleotide；NADH：還原型煙酰胺腺嘌呤二核苷酸reduced nicotinamide adenine dinucleotide；GTP：三磷酸鳥苷guanosine triphosphate；GDP：二磷酸鳥苷guanosine diphosphate；FAD：黃素腺嘌呤二核苷酸flavin adenine dinucleotide；FADH2：還原型黃素腺嘌呤二核苷酸reduced flavin adenine dinucleotide。

圖1 氨基酸氧化代謝途徑

Fig.1 The oxidative metabolism pathways of amino acids[21]

2.2 甘氨酸和丙氨酸——尿素的間接前體物

前期研究發(fā)現(xiàn)，采食粗蛋白質水平為20%、17%和14%飼糧的仔豬門靜脈谷氨酸凈吸收速率分別為-4.43、-5.65和-6.64 mg/min；門靜脈氨的凈吸收速率則分別為2.86、2.68和2.38 mg/min[23]。該結果與其他報道一致，即豬PDV中廣泛代謝谷氨酸等氨基酸，同時也產生大量的氨[4,17,20]。此外，采食上述3個蛋白質水平飼糧的仔豬門靜脈甘氨酸與丙氨酸的凈吸收量占總氨基酸凈吸收量的比例分別為38.2%、37.3%和37.0%；甘氨酸和丙氨酸在肝臟中的消耗量占總氨基酸代謝量的比例分別為52.0%、49.5%和43.8%。這一氨基酸代謝規(guī)律的發(fā)現(xiàn)引起人們對甘氨酸和丙氨酸的來源及代謝去路的深入思考。

傳統(tǒng)觀點認為絲氨酸是甘氨酸的主要前體物，而Wu[21]則提出不同的觀點，認為僅有10%左右的甘氨酸來源于絲氨酸；丙氨酸的前體物包括丙酮酸、絲氨酸和天門冬氨酸[24]。根據(jù)氨基酸的代謝轉化途徑[21,24](圖2)，推測PDV中廣泛代謝的氨基酸(如谷氨酸、谷氨酰胺和天門冬氨酸等)極有可能是甘氨酸和丙氨酸的重要前體物。為證實這一推測，利用血插管與15N穩(wěn)定性同位素示蹤技術發(fā)現(xiàn)，PDV中轉化為甘氨酸和丙氨酸的谷氨酸占谷氨酸代謝總量的比例約為30%。這一氨基酸代謝規(guī)律實質上反映了機體的一項重要自我保護機制：PDV中氨基酸代謝所產生的氨如果全部直接進入肝臟會造成氨的濃度過高，有可能引起肝損傷，而將其中一部分氨轉化為分子質量相對較小的甘氨酸和丙氨酸(分子質量分別為75和89 u，遠低于氨基酸的平均分子質量)，不僅能有效降低氨的濃度、減輕肝臟的氨負擔，同時又能發(fā)揮谷氨酸等氨基酸在PDV中的代謝燃料功能。

Berthiaume等[25]和Doepel等[26]先后報道肝臟會代謝大量的甘氨酸和丙氨酸，且甘氨酸是重要的生氨氨基酸[27]；丙氨酸會增加饑餓大鼠肝細胞尿素的合成[28]，丙氨酸也是甘氨酸代謝過程的重要參與者[29]。以上研究表明，甘氨酸和丙氨酸與肝臟尿素合成密切相關[27-29]，但尚未有報道證實甘氨酸和丙氨酸是尿素合成的重要氮來源。結合前人的研究報道，推測在肝臟中多余的甘氨酸和丙氨酸用來合成尿素。為證實這一推測，利用血插管與15N穩(wěn)定性同位素示蹤技術開展了甘氨酸和丙氨酸在肝臟中代謝去路的研究，研究表明甘氨酸和丙氨酸是尿素的重要間接前體物[30]。

Ile：異亮氨酸isoleucine；Leu：亮氨酸leucine；Lys：賴氨酸lysine；Phe：苯丙氨酸phenylalanine；Tyr：酪氨酸t(yī)yrosine；Trp：色氨酸t(yī)ryptophan；Acetyl-CoA：乙酰輔酶A；CO2：二氧化碳carbon dioxide；NH3：氨ammonia；Choline：膽堿；Threonine：蘇氨酸；Glycine：甘氨酸；Serine：絲氨酸；Alanine：丙氨酸；Pyruvate：丙酮酸；Gluc：葡萄糖glucose；Val：纈氨酸valine；Met：蛋氨酸methionine；Oxaloacetate：草酰乙酸；Aspartate：天門冬氨酸；Asparagine：天門冬酰胺；α-Ketoglutarate：α-酮戊二酸；BCAA：支鏈氨基酸branched-chain amino acids；Glutamate：谷氨酸；His：組氨酸histidine；Glutamine：谷氨酰胺；Proline：脯氨酸；Ornithine：鳥氨酸；Arginine：精氨酸；Cys：半胱氨酸cysteine；D3PG：D-3-磷酸甘油酸D-3-phosphoglycerate；HYP：羥(基)脯氨酸 hydroxyproline；TF：四氫葉酸 tetrahydrofolic acid。

圖2 氨基酸的代謝轉化途徑

Fig.2 The pathways of metabolic transformation between amino acids[21,24]

3 氨基酸代謝燃料功能替代機制

綜上所述，減少PDV中尿素前體物(主要包括氨、甘氨酸和丙氨酸)的生成是降低尿素合成以及尿氮排放量的關鍵，而提供氨基酸代謝燃料替代物以降低氨基酸的氧化代謝速率是實現(xiàn)這一目標的重要途徑。有關氨基酸代謝燃料替代物的探索開始于20世紀90年代，但由于研究甚少，迄今為止尚未取得突破性進展。除谷氨酸/谷氨酰胺外，葡萄糖也是各類組織細胞的重要燃料物質，但通常情況下葡萄糖難以抑制谷氨酸/谷氨酰胺的氧化分解[17]；不僅如此，谷氨酸/谷氨酰胺還會顯著降低葡萄糖的氧化代謝速率[31-33]。因此，如何提高葡萄糖在PDV中的氧化供能效率是豬氮減排研究亟待解決的科學問題。

氨基酸、脂肪、葡萄糖的氧化路徑雖不同，但最后都匯聚于同一點，即TCA循環(huán)[34](圖3)。乙酰輔酶A、丙酮酸、草酰乙酸、琥珀酰輔酶A、延胡索酸和α-酮戊二酸是氨基酸進入TCA循環(huán)的中間產物[21]，其中丙酮酸在三大物質的代謝聯(lián)系中起重要的樞紐作用，若丙酮酸代謝發(fā)生異常將會導致眾多疾病的發(fā)生，包括糖尿病、肥胖[35]、線粒體功能紊亂[36]、心臟衰竭[37]、神經退行性疾病[38]和癌癥[39]。研究表明，丙酮酸是氨基酸氧化代謝的重要調控因子[40-42]。鑒于丙酮酸在三大物質代謝過程中所發(fā)揮的重要作用，推測丙酮酸有可能是氨基酸和葡萄糖代謝的共同調控靶點，促進丙酮酸在PDV中的氧化分解有望增加葡萄糖的氧化代謝速率、抑制氨基酸的代謝燃料功能，從而降低尿素前體物(氨、甘氨酸和丙氨酸)的生成以及尿素的合成。

Lipids：脂類；fatty acids：脂肪酸；acyl-CoA：酰基輔酶A；acetyl-CoA：乙酰輔酶A；carbohydrates：碳水化合物；glucose：葡萄糖；ADP：二磷酸腺苷adenosine diphosphate；ATP：三磷酸腺苷adenosine triphosphate；glycolysis：醣酵解；pyruvate：丙酮酸；proteins：蛋白質；amino acids：氨基酸；transamination：轉氨基；deamination：脫氨；CO2：二氧化碳carbon dioxide；TCA cycle：三羧酸循環(huán)；β-oxidation：β-氧化；NADH：還原型煙酰胺腺嘌呤二核苷酸reduced nicotinamide adenine dinucleotide；FADH2：還原型黃素腺嘌呤二核苷酸reduced flavin adenine dinucleotide；Pi：磷酸基；ETC：電子傳遞鏈electron transfer chain。

圖3 三大營養(yǎng)物質氧化代謝途徑

Fig.3 The oxidative metabolism pathways of three major nutrients[34]

哺乳動物細胞中，丙酮酸脫氫酶復合體(pyruvate dehydrogenase complex，PDC)負責催化丙酮酸轉化為乙酰輔酶A。PDC由3種酶[丙酮酸脫氫酶(pyruvate dehydrogenase，PDH)、二氫硫辛酰轉乙?；?、二氫硫辛酸脫氫酶]和6種輔助因子[焦磷酸硫胺素、硫辛酸、黃素腺嘌呤二核苷酸(flavin adenine dinucleotide，F(xiàn)AD)、煙酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide，NAD)、輔酶A(coenzyme A，CoA)和Mg2+]組成。PDH上游調控因子主要包括丙酮酸脫氫酶激酶(pyruvate dehydrogenase kinase，PDK)和丙酮酸脫氫酶磷酸酶(pyruvate dehydrogenase phosphatase，PDP)，調控機制如圖4所示[43]。PDK1通過磷酸化PDH分子上的絲氨酸殘基(包括Ser-293、Ser-300、Ser-232)抑制其活性，而PDP則通過去磷酸化恢復PDH以及PDC的活性[44]。酪氨酸磷酸化將分別激活PDK活性和抑制PDP活性[45]。綜上所述，PDK/PDP/PDH軸極有可能是葡萄糖/氨基酸的調控靶點。

Gluconeogenesis：糖異生；cytosol：細胞溶質；glucose：葡萄糖；PEP：磷酸烯醇式丙酮酸phosphoenolpyruvate；pyruvate：丙酮酸；glycolysis：糖酵解；lipid biosynthesis：脂類生物合成；acetyl-CoA：乙酰輔酶A；CO2：二氧化碳carbon dioxide；H+：氫離子；NAD+：煙酰胺腺嘌呤二核苷酸nicotinamide adenine dinucleotide；NADH：還原型煙酰胺腺嘌呤二核苷酸reduced nicotinamide adenine dinucleotide；mitochondrial matrix：線粒體基質；PDC active：有活性的丙酮酸脫氫酶復合體active pyruvate dehydrogenase complex；PDC inactive：無活性的丙酮酸脫氫酶復合體inactive pyruvate dehydrogenase complex；PDK：丙酮酸脫氫酶激酶pyruvate dehydrogenase kinase；isoenzymes：同功異構酶；PDP：丙酮酸脫氫酶磷酸酶pyruvate dehydrogenase phosphatase；insulin：胰島素：Ca2+：鈣離子；ATP：三磷酸腺苷adenosine triphosphate；P1-3：磷酸基1-3；TCA cycle：三羧酸循環(huán)。

圖4 丙酮酸脫氫酶復合體調節(jié)機制

Fig.4 The regulatory mechanisms of pyruvate dehydrogenase complex[43]

丙酮酸氧化代謝速率隨PDC活性的升高而提高[46]。小分子物質二氯乙酸(dichloroacetate，DCA)具有誘導細胞自噬、降低細胞增殖的重要功能。此外，研究表明DCA通過抑制PDK活性來激活PDH活性，從而降低糖酵解比例、提高葡萄糖的氧化代謝速率[47-48]。谷氨酰胺氧化代謝速率隨葡萄糖氧化代謝速率的升高而降低[49]。研究表明，促進丙酮酸的氧化代謝將導致谷氨酸脫氫酶的活性降低，從而降低來源于谷氨酰胺的乙酰輔酶A的生成[49]。由此可見，通過調控丙酮酸/葡萄糖氧化代謝速率來抑制氨基酸代謝燃料功能是可行的。

4 小 結

綜上所述，在PDV中異常增加的甘氨酸和丙氨酸歸因于谷氨酸等氨基酸的過度代謝，甘氨酸和丙氨酸是肝臟尿素合成的重要前體物。降低氨基酸的氧化代謝速率是減少尿素合成前體物和肝臟尿素合成的關鍵。促進丙酮酸/葡萄糖在豬PDV中的供能效率有望增加葡萄糖的氧化代謝速率、抑制氨基酸的代謝燃料功能，從而減少尿素前體物的生成以及尿氮排放量，而PDK/PDP/PDH軸可能是丙酮酸氧化代謝的調控靶點。雖然在體外試驗、老鼠試驗以及人類臨床試驗上已經證實通過促進丙酮酸/葡萄糖的氧化代謝速率來降低氨基酸的供能效率是可行的，但豬體代謝與細胞、老鼠和人類相比差異極大，且研究目的不同，因此這一假說需要開展大量的體內和體外試驗進行驗證。

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Author, SUN Zhihong, professor, E-mail: sunzh2002cn@aliyun.com

(責任編輯 李慧英)

A New Hypothesis for the Mechanism of Metabolic Saving of Amino Acids of Pigs

SUN Zhihong1LI Mao1XU Qingqing1YIN Yulong2ZHU Weiyun3JIANG Qingyan4HUANG Feiruo5

(1. Laboratory for Bio-Feed and Animal Nutrition, Southwest University, Chongqing 400715, China; 2. Institute of Subtropical Agriculture, the Chinese Academy of Sciences, Changsha 410125, China; 3. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; 4. College of Animal Science and Technology, Huanan Agricultural University, Guangzhou 510642, China; 5. College of Animal Science and Technology, Huazhong Agricultural University,Wuhan 430070, China)

Urinary nitrogen excretion accounts for 60% to 70% of the total nitrogen excretion of pigs. The production rate of urea, which is the main nitrogen-containing substance in the urine, to a large extent determines the urinary nitrogen and total nitrogen excretion. Therefore, declining the production rate of urea in liver of pigs is a fundamental approach for reducing total nitrogen excretion. This review summarized the existing nutrition regulatory measures for reducing nitrogen excretion in pigs, characterized the nitrogen direct precursors (ammonia) and indirect precursors (glycine and alanine) of urea synthesis in liver, and the mechanism of metabolic fuel function substitution of amino acid (AA). On this basis, a new hypothesis for the regulatory mechanism of metabolic saving of AA was proposed, the essence of which is to promote the efficiency of substances like as pyruvate/glucose being as metabolic fuel, decline metabolic rate of AA especially of glutamate, decrease the net flow of nitrogen precursors for urea synthesis in portal vein, urea synthesis in liver and urinary nitrogen excretion.[ChineseJournalofAnimalNutrition, 2016, 28(11)：3369-3376]

nitrogen excretion; amino acids; metabolic saving; pyruvate dehydrogenase

2016-04-11

國家重點基礎研究發(fā)展計劃(2013CB127300)；農業(yè)部"948"項目(2015Z74)；國家科技支撐計劃課題(2012BAD14B18)；重慶市自然科學基金(cstc2012jjA80001)

孫志洪(1975—)，男，四川成都人，教授，碩士生導師，博士，從事動物營養(yǎng)研究。E-mail: sunzh2002cn@aliyun.com

10.3969/j.issn.1006-267x.2016.11.001

S828

A

1006-267X(2016)11-3369-08