幼龄反刍动物瘤胃上皮细胞β-羟基丁酸代谢与调控机制

doi:10.11843/j.issn.0366-6964.2020.04.002

摘要/Abstract

摘要： β-羟基丁酸（β-hydroxybutyric acid，BHBA）是酮体的主要成分之一，在反刍动物瘤胃中由微生物发酵产生的丁酸在瘤胃上皮细胞中氧化生成，BHBA对反刍动物瘤胃上皮细胞的代谢与增殖具有重要调控作用。近年来，有关BHBA研究多集中在肝脏生酮、奶牛酮病及泌乳等方面，关于BHBA与幼龄反刍动物瘤胃上皮细胞生长发育之间的关系及内在机制研究很少。本文重点针对BHBA在瘤胃上皮的生成、转运，以及BHBA作为信号分子调控瘤胃上皮细胞代谢与增殖的分子机制进行综述，这对于丰富瘤胃发育及调控理论与幼龄反刍动物培育营养策略具有重要意义。

关键词: β-羟基丁酸, 幼龄反刍动物, 瘤胃上皮细胞, 生酮作用, 细胞增殖

Abstract: Beta-hydroxybutyric acid (BHBA) is one of the main components of ketones. BHBA is a metabolite of butyrate, which is produced by rumen microbial fermentation, in rumen epithelial cells. BHBA plays an important regulatory role in rumen epithelial cells proliferation and metabolism of ruminants. In recent years, most studies on BHBA have focused on liver ketogenesis, dairy cow ketosis and its effect on lactation. Little information is available in the literature regarding to the relationship and inherent mechanisms between BHBA and rumen epithelial cell growth in young ruminants. This review focuses on the formation and transport of BHBA in rumen epithelial cells, as well as the molecular mechanism of BHBA as a signal molecule regulating the metabolism and proliferation of rumen epithelial cells. This is of great significance to enrich the theory on regulation and development of rumen and the nutritional strategy for the rearing of young ruminants.

Key words: beta-hydroxybutyric acid, young ruminants, rumen epithelial cell, ketogenesis, cell proliferation

中图分类号:

S811.6

庄一民, 刁其玉, 张乃锋. 幼龄反刍动物瘤胃上皮细胞β-羟基丁酸代谢与调控机制[J]. 畜牧兽医学报, 2020, 51(4): 660-669.

ZHUANG Yimin, DIAO Qiyu, ZHANG Naifeng. Metabolism and Regulation Mechanism of Beta-hydroxybutyric Acid in Ruminal Epithelium Cells of Young Ruminants[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(4): 660-669.

参考文献 68

[1]	孙志鹏,李启涛,孙美涵,等.β-羟丁酸对奶牛腺垂体细胞GH和PRL的影响及机制[C]//中国畜牧兽医学会兽医内科与临床诊疗学分会第八届代表大会暨学术研讨会论文集.大庆:中国畜牧兽医学会兽医内科与临床诊疗学分会,2015.SUN Z P,LI Q T,SUN M H,et al.Effects of beta-hydroxybutyric acid on GH and PRL in pituitary cells in dairy cows[C]//Congress and Academic Seminar of Veterinary Medicine and Clinical Diagnosis Branch of China Animal Husbandry and Veterinary Association.Daqing:Chinese society of Animal Husbandry and Veterinary Medicine,2015.(in Chinese)
[2]	文静,付守鹏,柳巨雄.β-羟丁酸对中枢神经系统的作用及机制研究进展[J].中国畜牧兽医,2012,39(2):106-110.WEN J,FU S P,LIU J X.Research progress on the roles of β-hydroxybutyric acid played in central nervous system and mechanism[J]. China Animal Husbandry & Veterinary Medicine,2012,39(2):106-110.(in Chinese)
[3]	RANARAJA U,CHO K H,PARK M N,et al.Genetic parameter estimation for milk β-hydroxybutyrate and acetone in early lactation and its association with fat to protein ratio and energy balance in Korean Holstein cattle[J].Asian-Australas J Anim Sci, 2018,31(6):798-803.
[4]	KADOCHI Y,MORI S,FUJIWARA-TANI R,et al.Remodeling of energy metabolism by a ketone body and medium-chain fatty acid suppressed the proliferation of CT26 mouse colon cancer cells[J].Oncol Lett,2017,14(1):673-680.
[5]	吕小康,王杰,刁其玉,等.过氧化物酶体增殖物激活受体调控幼龄反刍动物瘤胃的生酮作用及其机制[J].动物营养学报,2018,30(4):1238-1244.LYU X K,WANG J,DIAO Q Y,et al.Peroxisome proliferator-activated receptors:regulation in ketogenesis of young ruminants and its mechanisms[J].Chinese Journal of Animal Nutrition,2018,30(4):1238-1244.(in Chinese)
[6]	LANE M A,BALDWIN IV R L,JESSE B W.Developmental changes in ketogenic enzyme gene expression during sheep rumen development[J].J Anim Sci,2002,80(6):1538-1544.
[7]	CONNOR E E,BALDWIN VI R L,LI C J,et al.Gene expression in bovine rumen epithelium during weaning identifies molecular regulators of rumen development and growth[J].Funct Integr Genomics,2013,13(1):133-142.
[8]	SHIMAZU T,HIRSCHEY M D,NEWMAN J,et al.Suppression of oxidative stress by β-hydroxybutyrate,an endogenous histone deacetylase inhibitor[J].Science,2013,339(6116):211-214.
[9]	王银龙,贺志锐,刘强,等.亚临床酮病奶牛血液生化指标的测定[J].动物医学进展,2014,35(3):128-131.WANG Y L,HE Z R,LIU Q,et al.Determination of blood biochemical indexes in dairy cows with subclinical ketosis[J]. Progress in Veterinary Medicine,2014,35(3):128-131.(in Chinese)
[10]	GOMEZ-INSUASTI A S,GRANJA-SALCEDO Y T,ROSSI L G,et al.Effect of soybean oil availabilities on rumen biohydrogenation and duodenal flow of fatty acids in beef cattle fed a diet with crude glycerine[J].Arch Anim Nutr,2018, 72(4):308-320.
[11]	DARWIN,BARNES A,CORD-RUWISCH R.In vitro rumen fermentation of soluble and non-soluble polymeric carbohydrates in relation to ruminal acidosis[J].Ann Microbiol,2018,68(1):1-8.
[12]	刘婷,李发弟,王维民,等.不同日龄补饲开食料对湖羊羔羊瘤胃形态及表皮生长相关基因表达的影响[J].畜牧兽医学报, 2016,47(12):2441-2449.LIU T,LI F D,WANG W M,et al.Effects of starter feeding on rumen papilla genes expression involved in cellular growth and morphology in Hu lamb at different ages[J].Acta Veterinaria et Zootechnica Sinica,2016,47(12):2441-2449.(in Chinese)
[13]	IMANI M,MIRZAEI M,BAGHBANZADEH-NOBARI B,et al.Effects of forage provision to dairy calves on growth performance and rumen fermentation:a meta-analysis and meta-regression[J].J Dairy Sci,2017,100(2):1136-1150.
[14]	YU H N,LI R,HUANG H Y,et al.Short-chain fatty acids enhance the lipid accumulation of 3T3-L1 cells by modulating the expression of enzymes of fatty acid metabolism[J].Lipids,2018,53(1):77-84.
[15]	BHATIA S K,YANG Y H.Microbial production of volatile fatty acids:current status and future perspectives[J].Rev in Environ Sci Bio/Technol,2017,16(2):327-345.
[16]	李宁,程喜荣.奶牛酮病的发病机理研究概述[J].中国牛业科学,2013,39(1):46-48.LI N,CHENG X R.Pathogenesis of ketosis in dairy cattle[J].China Cattle Science,2013,39(1):46-48.(in Chinese)
[17]	NAEEM A,DRACKLEY J K,STAMEY J,et al.Role of metabolic and cellular proliferation genes in ruminal development in response to enhanced plane of nutrition in neonatal Holstein calves[J].J Dairy Sci,2012,95(4):1807-1820.
[18]	郭冬生,彭小兰.反刍动物挥发性脂肪酸消化代谢规律刍议[J].畜牧与饲料科学,2005,26(1):1-3.GUO D S,PENG X L.A review on digestion and metabolism of volatile fatty acids in ruminants[J].Animal Husbandry and Feed Science,2005,26(1):1-3.(in Chinese)
[19]	DIJKSTRA J,BOER H,VAN BRUCHEM J,et al.Absorption of volatile fatty acids from the rumen of lactating dairy cows as influenced by volatile fatty acid concentration,pH and rumen liquid volume[J].Brit J Nutr,1993,69(2):385-396.
[20]	ASCHENBACH J R,BILK S,TADESSE G,et al.Bicarbonate-dependent and bicarbonate-independent mechanisms contribute to nondiffusive uptake of acetate in the ruminal epithelium of sheep[J].Am J Physiol Gastrointest Liver Physiol,2009, 296(5):G1098-G1107.
[21]	WVRMLI R,WOLFFRAM S,SCHARRER E.Inhibition of chloride absorption from the sheep rumen by nitrate[J].J Vet Med Ser A, 1987,34(1-10):476-479.
[22]	ASH R,BAIRD G D.Activation of volatile fatty acids in bovine liver and rumen epithelium.Evidence for control by autoregulation[J]. Biochem J,1973, 136(2):311-319.
[23]	PUCHALSKA P,CRAWFORD P A.Multi-dimensional roles of ketone bodies in fuel metabolism,signaling,and therapeutics[J]. Cell Metab,2017,25(2):262-284.
[24]	RESCIGNO T,CAPASSO A,TECCE M F.Involvement of nutrients and nutritional mediators in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression[J].J Cell Physiol,2018,233(4):3306-3314.
[25]	MA L,ZHAO M,ZHAO L S,et al.Effects of dietary neutral detergent fiber and starch ratio on rumen epithelial cell morphological structure and gene expression in dairy cows[J].J Dairy Sci,2017,100(5):3705-3712.
[26]	CHEN S W,CHOU C T,CHANG C C,et al.HMGCS2 enhances invasion and metastasis via direct interaction with pparα to activate src signaling in colorectal cancer and oral cancer[J].Oncotarget,2017,8(14):22460-22476.
[27]	汪水平,王文娟,谭支良.离体瘤胃上皮细胞在瘤胃代谢中的研究进展[J].家畜生态学报,2006,27(2):1-4.WANG S P,WANG W J,TAN Z L.Advance of isolated ruminal epithelial cells in the study of rumen metabolism[J].Acta Ecologiae Animalis Domastici,2006,27(2):1-4.(in Chinese)
[28]	TOGNINI P,MURAKAMI M,LIU Y,et al.Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet[J].Cell Metab,2017,26(3):523-538.
[29]	BOISON D.New insights into the mechanisms of the ketogenic diet[J].Curr Opin Neurol,2017,30(2):187-192.
[30]	HASAN-OLIVE M M,LAURITZEN K T,ALI M,et al.A ketogenic diet improves mitochondrial biogenesis and bioenergetics via the PGC1α-SIRT3-UCP2 axis[J].Neurochem Res,2019,44(1):22-37.
[31]	WANG X M,LIU Q,ZHOU J,et al.β hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats[J].Exp Anim,2017,66(2):177-182.
[32]	姜茂成,詹康,贡笑笑,等.不同pH和SCFAs对奶牛瘤胃上皮细胞SCFAs转运蛋白和GPR41表达的影响[J].中国农业大学学报,2018,23(10):63-70.JIANG M C,ZHAN K,GONG X X,et al.Effects of different pH and SCFAs on the expressions of SCFAs transport proteins and GPR41 in the rumen epithelial cells of dairy cow[J].Journal of China Agricultural University,2018,23(10):63-70.(in Chinese)
[33]	JAIN S K,MCVIE R.Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients[J].Diabetes,1999,48(9):1850-1855.
[34]	TIAN L P,YANG Z J,ZHANG C,et al.Correlation of physiological metabolism and rumen microbes in ruminants[J].Anim Husb Feed Sci,2017,9(4):200-203.
[35]	LI B B,ZHANG K,LI C,et al.Characterization and comparison of microbiota in the gastrointestinal tracts of the goat (Capra hircus) during preweaning development[J].Front Microbiol,2019,10:2125.
[36]	ZHAO C X,WANG Y Z,PENG Z C,et al.Subacute ruminal acidosis suppressed the expression of MCT1 in rumen of cows[J].J Cell Physiol,2019,234(7):11734-11745.
[37]	DE B LUZ M C,PEREZ M M,AZZALIS L A,et al.Evaluation of MCT1,MCT4 and CD147 genes in peripheral blood cells of breast cancer patients and their potential use as diagnostic and prognostic markers[J].Int J Mol Sci,2017,18(4):170.
[38]	PETERSEN C,NIELSEN M D,ANDERSEN E S,et al.MCT1 and MCT4 expression and lactate flux activity increase during white and brown adipogenesis and impact adipocyte metabolism[J].Sci Rep,2017,7(1):13101.
[39]	CASTELLS L,BACH A,ARIS A,et al.Effects of forage provision to young calves on rumen fermentation and development of the gastrointestinal tract[J].J Dairy Sci,2013,96(8):5226-5236.
[40]	史晓霞.NEFAs和BHBA诱导氧化应激对奶牛肝细胞NF-κB信号通路影响的研究[D].长春:吉林大学,2014.SHI X X.The study of NEFAs and BHBA inducing oxidative stress on NF-κB signaling pathway in calf hepatocytes[D]. Changchun:Jilin University,2014.(in Chinese)
[41]	DOEGE H,STAHL A.Protein-mediated fatty acid uptake:novel insights from in vivo models[J].Physiology,2006,21(4):259-268.
[42]	FROHNERT B I,HUI T Y,BERNLOHR D A.Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene[J].J Biol Chem,1999,274(7):3970-3977.
[43]	IJPENBERG A,TAN N S,GELMAN L,et al.In vivo activation of PPAR target genes by RXR homodimers[J].EMBO J,2014,23(10):2083-2091.
[44]	高景,齐智利.瘤胃上皮短链脂肪酸的吸收和代谢[J].动物营养学报,2018,30(4):1271-1278.GAO J,QI Z L.Absorption and metabolism of short chain fatty acids in ruminal epithelium[J].Chinese Journal of Animal Nutrition, 2018,30(4):1271-1278.(in Chinese)
[45]	MUYA M C,NHERERA F V,MILLER K A,et al.Effect of Megasphaera elsdenii NCIMB 41125 dosing on rumen development, volatile fatty acid production and blood β-hydroxybutyrate in neonatal dairy calves[J].J Anim Physiol Anim Nutr (Berl),2015, 99(5):913-918.
[46]	SAMIEI A,LIANG J B,GHORBANI G R,et al.Relationship between dietary energy level,silage butyric acid and body condition score with subclinical ketosis incidence in dairy cows[J].Adv Anim Vet Sci,2015,3(6):354-361.
[47]	HELENIUS T O,MISIOREK J O,NYSTRÖM J H,et al.Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism[J].Mol Biol Cell,2015,26(12):2298-2310.
[48]	李鹏,刘敏跃,龙淼,等.BHBA对体外培养犊牛肝细胞HMGCS基因表达的影响[J].饲料工业,2013,34(21):58-60.LI P,LIU M Y,LONG M,et al.Effect of β-hydroxybutyrate on expression of 3-hydroxy-3-methylglutaryl-coa synthase in bovine hepatocytes cultured in vitro[J].Feed Industry,2013,34(21):58-60.(in Chinese)
[49]	KATO D,SUZUKI Y,HAGA S,et al.Utilization of digital differential display to identify differentially expressed genes related to rumen development[J].Anim Sci J,2016,87(4):584-590.
[50]	SMITH F M,COFFEY J C,KELL M R,et al.A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch[J].Colorectal Dis,2005,7(6):563-570.
[51]	MALMUTHUGE N,LIANG G X,GUAN L L.Regulation of rumen development in neonatal ruminants through microbial metagenomes and host transcriptomes[J].Genome Biol,2019,20(1):172.
[52]	吕小康,解彪,黄文琴,等.早期饲喂对山羊羔羊瘤胃和小肠组织形态的影响[J].畜牧兽医学报,2019,50(5):1006-1015.LÜ X K,XIE B,HUANG W Q,et al.Effects of early feeding on rumen and small intestine morphology of goat kids[J].Acta Veterinaria et Zootechnica Sinica,2019,50(5):1006-1015.(in Chinese)
[53]	STEIN G S,STEIN J L,LIAN J B.Cell cycle and growth control[J].J Cell Biochem,1994,54(4):373-374.
[54]	卢劲晔,卢炜,刘静,等.IGF-1促进山羊瘤胃上皮细胞增殖的机制[J].南京农业大学学报,2014,37(5):106-110.LU J Y,LU W,LIU J,et al.Mechanism of IGF-1 on proliferation of rumen epithelium of goats in vitro[J].Journal of Nanjing Agricultural University,2014,37(5):106-110.(in Chinese)
[55]	薛文静.BHBA对大鼠下丘脑GHRH表达和分泌的影响及其机制[D].长春:吉林大学,2015.XUE W J.Effects and its mechanisms of BHBA on GHRH expression and secrection in rat hypothalamus[D].Changchun:Jilin University,2015.(in Chinese)
[56]	TAYLOR E S,POL-FACHIN L,LINS R D,et al.Conformational stability of the epidermal growth factor (EGF) receptor as influenced by glycosylation,dimerization and EGF hormone binding[J].Proteins,2017,85(4):561-570.
[57]	BEDFORD A,CHEN T,HUYNH E,et al.Epidermal growth factor containing culture supernatant enhances intestine development of early-weaned pigs in vivo:potential mechanisms involved[J].J Biotechnol,2015,196-197:9-19.
[58]	MENG J,DAI B,FANG B,et al.Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo[J].PLoS One,2010,5(11):e14124.
[59]	TOUEILLE M,SAINT-JEAN B,CASTROVIEJO M,et al.The elongation factor 1A:A novel regulator in the DNA replication/repair protein network in wheat cells?[J].Plant Physiol Biochem,2007,45(2):113-118.
[60]	STRICKER E M,ROWLAND N,SALLER C F,et al.Homeostasis during hypoglycemia:central control of adrenal secretion and peripheral control of feeding[J].Science,1977,196(4285):79-81.
[61]	QUABBE H J,BUMKE-VOGT C,IGLESIAS-ROZAS J R,et al.Hypothalamic modulation of growth hormone secretion in the rhesus monkey:evidence from intracerebroventricular infusions of glucose,free fatty acid,and ketone bodies[J].J Clin Endocrinol Metab,1991,73(4):765-770.
[62]	BOADO R,COLOMBO O,ZANINOVICH A A.Effects of diabetes,β-hydroxybutyric acid and metabolic acidosis on the pituitary-thyroid axis in the rat[J].J Endocrinol Invest,1985,8(2):107-111.
[63]	VAHID F,ZAND H,NOSRAT-MIRSHEKARLOU E,et al.The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases:a review[J].Gene,2015,562(1):8-15.
[64]	CANTLEY M D,ZANNETTINO A C W,BARTOLD P M,et al.Histone deacetylases (HDAC) in physiological and pathological bone remodelling[J].Bone,2017,95:162-174.
[65]	孟瑾,刘新利,车玲,等.组蛋白去乙酰化酶抑制剂TSA抑制结肠癌HT29细胞增殖作用的机制研究[J].消化肿瘤杂志:电子版,2019,11(2):88-93.MENG J,LIU X L,CHE L,et al.Effect and mechanism of histone deacetylase inhibitor TSA on the proliferation of colon cancer HT29 cells[J].Journal of Digestive Oncology:Electronic Version,2019,11(2):88-93.(in Chinese)
[66]	WU N Z,GU T T,LU L,et al.Roles of miRNA-1 and miRNA-133 in the proliferation and differentiation of myoblasts in duck skeletal muscle[J].J Cell Physiol,2019,234(4):3490-3499.
[67]	弓贺炜,刘承伟,梁炳生,等.过表达慢病毒载体介导miR-1转染L6细胞增殖分化及组蛋白去乙酰化酶的表达[J].中国组织工程研究,2019,23(13):2075-2080.GONG H W,LIU C W,LIANG B S,et al.Lentiviral vector-mediated overexpression of miRNA-1 in L6 myoblasts:cell proliferation,differentiation and histone deacetylase expression[J].Chinese Journal of Tissue Engineering Research,2019, 23(13):2075-2080.(in Chinese)
[68]	XIE Z Y,ZHANG D,CHUNG D J,et al.Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation[J].Mol Cell,2016,62(2):194-206.