LKB1-AMPKα-SIRT1信号通路在奶牛脂肪组织脂代谢中的调控作用
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摘要
奶牛脂肪细胞体积和数目的不断增加会导致脂肪组织脂代谢的紊乱,引起一系列相关慢性疾病如Ⅱ型糖尿病、酮病、脂肪肝、高脂血症等的发生,LKB1-AMPKα-SIRT1信号通路在奶牛脂肪组织脂代谢中起着重要的调控作用。单磷酸腺苷活化蛋白激酶(AMPK)是比较保守的丝氨酸/苏氨酸激酶,在调节能量代谢中起着枢纽作用。肝激酶B1(LKB1)属于一种丝氨酸激酶,是AMPKα的上游激酶,可参与细胞内能量代谢等多种生物活动。沉默信息调节因子1(SIRT1)是一种NAD+依赖的组蛋白去乙酰化酶,可通过去乙酰化LKB1增加AMPKα的活性。就LKB1-AMPKα-SIRT1信号转导通路在奶牛脂肪组织脂代谢紊乱中的调控机制作一综述,旨在为下一步研究奶牛脂代谢相关信号通路调控机理提供依据。
The increasing volume and number of adipocyte leads to disorder of lipid metabolism in adipose tissue,which causes different chronic diseases such as type II diabetes,ketosis,fatty liver,and hyperlipidemia. The LKB1-AMPKα-SIRT1 signal pathway plays important regulating role in the lipid metabolism of dairy cows adipose tissue. AMPK as conservative serine/threonine kinase plays a pivotal role in the regulation of energy metabolism. LKB1(liver kinase B1)is a serine/threonine kinase,an upstream kinase of AMPKα,participates in various biological activities such as intracellular energy metabolism. Silencing information regulator factor 1(SIRT1),a kind of NAD+-dependent histone deacetylase,can increase AMPKα activity by deactivating LKB1. This article reviews the regulation mechanisms of LKB1-AMPKα-SIRT1 signal transduction pathways in lipid metabolism of adipose tissue in dairy cows,aiming at providing a basis for further studying the regulating mechanisms of related signal pathways in the lipid metabolism of dairy cows.
The increasing volume and number of adipocyte leads to disorder of lipid metabolism in adipose tissue,which causes different chronic diseases such as type II diabetes,ketosis,fatty liver,and hyperlipidemia. The LKB1-AMPKα-SIRT1 signal pathway plays important regulating role in the lipid metabolism of dairy cows adipose tissue. AMPK as conservative serine/threonine kinase plays a pivotal role in the regulation of energy metabolism. LKB1(liver kinase B1)is a serine/threonine kinase,an upstream kinase of AMPKα,participates in various biological activities such as intracellular energy metabolism. Silencing information regulator factor 1(SIRT1),a kind of NAD+-dependent histone deacetylase,can increase AMPKα activity by deactivating LKB1. This article reviews the regulation mechanisms of LKB1-AMPKα-SIRT1 signal transduction pathways in lipid metabolism of adipose tissue in dairy cows,aiming at providing a basis for further studying the regulating mechanisms of related signal pathways in the lipid metabolism of dairy cows.
引文
[1]Deguchi A, Miyoshi H, Kojima Y, et al. LKB1 suppresses p21-activated kinase-1(PAK1)by phosphorylation of thr(109)in the p21-binding domain[J]. Journal of Biological Chemistry, 2010,285(24):18283-18290.
[2]陈标,满玉蓉,高柳玲,等. AMPK调控能量代谢研究进展[J].生物学杂志, 2017, 34(5):78-82.
[3]李莉萍,曾卫民,郭明日. SIRT1的生物学功能及其在胰岛素抵抗中的作用[J].生命科学研究, 2010, 14(4):372-376.
[4]韩洁. LKB1抑制脂肪生成和分化的机制研究[D].天津:天津医科大学, 2016.
[5]Zeqiraj E, Filippi BM, Deak M, et al. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation[J]. Science, 2009, 326(5960):1707-1711.
[6]Zhang BB, Zhou G, Li C. AMPK:an emerging drug target for diabetes and the metabolic syndrome[J]. Cell Metabolism, 2009,9(5):407-416.
[7]张霞,孙琳琳,钟殿胜. LKB1-AMPK-mTOR信号传导通路在肿瘤中的研究进展[J].中国肺癌杂志, 2011,(8):685-688.
[8]Eggers C, Kline E, Zhong D, et al. STE20-related kinase adaptor proteinα(STRADα)regulates cell polarity and invasion through PAK1 signal in LKB1-null cells[J]. Journal of Biological Chemistry, 2012, 287(22):18758-18768.
[9]Ková?ik J, KalafováA, Tu?imováE. Relations between selected indicatorsofbloodandmilkofdairycowswithmetabolic disorders[J]. Journal of Microbiology Biotechnology&Food Sciences, 2013,(2):1980-1987.
[10]李心慰.乙酸、非酯化脂肪酸、生长激素和催乳素调控奶牛肝细胞脂代谢的信号机制[D].长春:吉林大学, 2013.
[11]Hardie DG. AMPK:positive and negative regulation, and its role in whole-body energy homeostasis[J]. Current Opinion in Cell Biology, 2015(33):1-7.
[12]耿凤豪,张鹏,董玲,等. AMPK-能量代谢感受器与可激活AMPK相关的药物研究进展[J].心脏杂志, 2014(1):97-100.
[13]张玉佩,杨钦河,邓远军,等.参苓白术散对高脂饮食诱导的NAFLD大鼠肝组织超微结构及AMPKα磷酸化的影响[J].中药药理与临床, 2016(1):6-10.
[14]Lim JH, Gerharthines Z, Dominy JE, et al. Oleic acid stimulates complete oxidation of fatty acids through protein kinase a-dependent activation of sirt1-pgc1αcomplex[J]. Journal of Biological Chemistry, 2013, 288(10):7117-7126.
[15]Guarente L. Sirtuins as potential targets for metabolic syndrome[J]. Nature, 2006, 444(7121):868-874.
[16]Ramsey K, Mills K, Satoh A, et al. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing(BESTO)mice[J].Aging Cell, 2008, 7(1):78-88.
[17]Kim H, Mendez R, Chen X, et al. Lysine acetylation of crebh regulates fasting-induced hepatic lipid metabolism[J]. Molecular&Cellular Biology, 2016, 35(24):4121-4134.
[18]邵芳,郁建锋,张燕萍,等. SIRT1基因的表达调控及对动物脂类代谢的功能[J].常熟理工学院学报, 2015, 29(4):8-14.
[19]邓清华. NEFAs对犊牛原代肝细胞糖脂代谢的调控机制[D].长春:吉林大学, 2015.
[20]倪鸣,王金焱,王璟.白色脂肪组织棕色化调控机制的研究进展[J].医学研究生学报, 2015(7):771-775.
[21]秦佑.树豆酮酸A抑制3T3-L1脂肪细胞分化及调控其脂质代谢的作用研究[D].广州:广州中医药大学, 2016.
[22]张世奇. PLIN1对奶牛脂肪细胞脂代谢及炎性细胞因子合成的影响[D].长春:吉林大学, 2017.
[23]黄文钰,李向平.脂肪细胞三酰甘油分解代谢相关调节的研究进展[J].临床与病理杂志, 2013, 33(3):230-234.
[24]宋宇宙.牛蒡子苷元通过AMPK信号通路调节脂肪代谢的作用研究[D].广州:广州中医药大学, 2017.
[25]殷立恒. PRL、GC对奶牛脂肪细胞和肝细胞脂代谢的影响[D].长春:吉林大学, 2015.
[26]Cant?óC, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1activity[J]. Nature, 2009, 458(7241):1056-1060.
[27]梁舒.小檗碱通过Sirt1改善3T3--L1脂肪细胞糖代谢的机制研究[D].南京:南京中医药大学, 2017.
[28]Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinasedevelopment of the energy sensor concept[J]. Journal of Physiology, 2010, 574(1):7-15.
[29]孟胜喜,冯琴,彭景华,等. BZL方对游离脂肪酸诱导HepG2细胞脂肪沉积和LKB1-AMPK-ACC信号传导通路的影响[J].中华中医药杂志, 2014(5):1391-1396.
[30]匡霞,陆付耳,易屏.小檗碱对HepG2胰岛素抵抗细胞模型中LKB1-AMPK-TORC2信号网络的影响[J].中国中西医结合消化杂志, 2015(7):467-471.
[31]Li X, Li X, Chen H, et al. Non-esterified fatty acids activate the AMP-activated protein kinase signaling pathway to regulate lipid metabolism in bovine hepatocytes[J]. Cell Biochemistry&Biophysics, 2013, 67(3):1157-1169.
[32]Li X, Li Y, Ding H, et al. Insulin suppresses the AMPK signaling pathway toregulatelipidmetabolism inprimarycultured hepatocytes of dairy cows[J]. Journal of Dairy Research, 2018,(85):157-162.
[33]高晓娜,郭小权.一磷酸腺苷激活的蛋白激酶对动物糖脂代谢的调节作用[J].动物营养学报, 2017, 29(12):4287-4294.
[34]李琳,郑卓,贺红专. PPARγ基因调控猪脂肪沉积研究进展[J].中国猪业, 2016, 11(8):57-60.
[35]杜希良. miR-181a对犊牛原代肝细胞糖脂代谢稳态的调控机制[D].长春:吉林大学, 2016.
[36]Bellet MM, Nakahata Y, Boudjelal M, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1[J]. Proc Natil Acad Sci USA, 2013, 110(9):3333-3338.
[37]Liu L, Li X, Li Y, et al. Effects of nonesterified fatty acids on the synthesis and assembly of very low density lipoprotein in bovine hepatocytes in vitro[J]. Journal of Dairy Science, 2014, 97(3):1328-1335.
[38]Ito M, Nagasawa M, Omae N, et al. A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes[J]. Journal of Lipid Research, 2013, 54(6):1531-1540.
[39]Zhang M, Zhang S, Hui Q, et al.β-hydroxybutyrate facilitates fatty acids synthesis mediated by sterol regulatory element-binding protein1 in bovine mammary epithelial cells[J]. Cellular Physiology&Biochemistry, 2015, 37(6):2115-2124.
[40]Chau MD, Gao J, Yang Q, et al. Fibroblast growth factor 21regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway[J]. Proc Natil Acad Sci USA, 2010, 107(28):12553-12558.
[41]Li X, Chen H, Guan Y, et al. Acetic acid activates the AMPactivated protein kinase signal pathway to regulate lipid metabolism in bovine hepatocytes[J]. Journal of Steroid Biochemistry&Molecular Biology, 2013, 138(7):445-454.
[42]王怡,刘宗平.奶牛围产期脂肪代谢的研究进展[J].畜牧与兽医, 2013, 45(4):98-101.
[43]孙艳发,张敏,李焰,等.维生素E对动物脂肪代谢调控的研究进展[J].中国畜牧杂志, 2015, 51(13):82-85.
[44]Shi X, Li D, Deng Q, et al. Acetoacetic acid induces oxidative stress to inhibit the assembly of very low density lipoprotein in bovine hepatocytes[J]. Journal of Dairy Research, 2016, 83(4):442-446.
[45]Ono K, Horie T, Nishino T, et al. MicroRNA-33a/b in lipid metabolism-novel “thrifty” models[J]. Circulation Journal Official Journal of the Japanese Circulation Society, 2015, 79(2):278-284.
[46]靳青,魏晨,张相伦,等. miRNA-33对胆固醇合成的调控作用及其在肉牛上的研究进展[J].草食家畜, 2018(4):5-9.
[2]陈标,满玉蓉,高柳玲,等. AMPK调控能量代谢研究进展[J].生物学杂志, 2017, 34(5):78-82.
[3]李莉萍,曾卫民,郭明日. SIRT1的生物学功能及其在胰岛素抵抗中的作用[J].生命科学研究, 2010, 14(4):372-376.
[4]韩洁. LKB1抑制脂肪生成和分化的机制研究[D].天津:天津医科大学, 2016.
[5]Zeqiraj E, Filippi BM, Deak M, et al. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation[J]. Science, 2009, 326(5960):1707-1711.
[6]Zhang BB, Zhou G, Li C. AMPK:an emerging drug target for diabetes and the metabolic syndrome[J]. Cell Metabolism, 2009,9(5):407-416.
[7]张霞,孙琳琳,钟殿胜. LKB1-AMPK-mTOR信号传导通路在肿瘤中的研究进展[J].中国肺癌杂志, 2011,(8):685-688.
[8]Eggers C, Kline E, Zhong D, et al. STE20-related kinase adaptor proteinα(STRADα)regulates cell polarity and invasion through PAK1 signal in LKB1-null cells[J]. Journal of Biological Chemistry, 2012, 287(22):18758-18768.
[9]Ková?ik J, KalafováA, Tu?imováE. Relations between selected indicatorsofbloodandmilkofdairycowswithmetabolic disorders[J]. Journal of Microbiology Biotechnology&Food Sciences, 2013,(2):1980-1987.
[10]李心慰.乙酸、非酯化脂肪酸、生长激素和催乳素调控奶牛肝细胞脂代谢的信号机制[D].长春:吉林大学, 2013.
[11]Hardie DG. AMPK:positive and negative regulation, and its role in whole-body energy homeostasis[J]. Current Opinion in Cell Biology, 2015(33):1-7.
[12]耿凤豪,张鹏,董玲,等. AMPK-能量代谢感受器与可激活AMPK相关的药物研究进展[J].心脏杂志, 2014(1):97-100.
[13]张玉佩,杨钦河,邓远军,等.参苓白术散对高脂饮食诱导的NAFLD大鼠肝组织超微结构及AMPKα磷酸化的影响[J].中药药理与临床, 2016(1):6-10.
[14]Lim JH, Gerharthines Z, Dominy JE, et al. Oleic acid stimulates complete oxidation of fatty acids through protein kinase a-dependent activation of sirt1-pgc1αcomplex[J]. Journal of Biological Chemistry, 2013, 288(10):7117-7126.
[15]Guarente L. Sirtuins as potential targets for metabolic syndrome[J]. Nature, 2006, 444(7121):868-874.
[16]Ramsey K, Mills K, Satoh A, et al. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing(BESTO)mice[J].Aging Cell, 2008, 7(1):78-88.
[17]Kim H, Mendez R, Chen X, et al. Lysine acetylation of crebh regulates fasting-induced hepatic lipid metabolism[J]. Molecular&Cellular Biology, 2016, 35(24):4121-4134.
[18]邵芳,郁建锋,张燕萍,等. SIRT1基因的表达调控及对动物脂类代谢的功能[J].常熟理工学院学报, 2015, 29(4):8-14.
[19]邓清华. NEFAs对犊牛原代肝细胞糖脂代谢的调控机制[D].长春:吉林大学, 2015.
[20]倪鸣,王金焱,王璟.白色脂肪组织棕色化调控机制的研究进展[J].医学研究生学报, 2015(7):771-775.
[21]秦佑.树豆酮酸A抑制3T3-L1脂肪细胞分化及调控其脂质代谢的作用研究[D].广州:广州中医药大学, 2016.
[22]张世奇. PLIN1对奶牛脂肪细胞脂代谢及炎性细胞因子合成的影响[D].长春:吉林大学, 2017.
[23]黄文钰,李向平.脂肪细胞三酰甘油分解代谢相关调节的研究进展[J].临床与病理杂志, 2013, 33(3):230-234.
[24]宋宇宙.牛蒡子苷元通过AMPK信号通路调节脂肪代谢的作用研究[D].广州:广州中医药大学, 2017.
[25]殷立恒. PRL、GC对奶牛脂肪细胞和肝细胞脂代谢的影响[D].长春:吉林大学, 2015.
[26]Cant?óC, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1activity[J]. Nature, 2009, 458(7241):1056-1060.
[27]梁舒.小檗碱通过Sirt1改善3T3--L1脂肪细胞糖代谢的机制研究[D].南京:南京中医药大学, 2017.
[28]Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinasedevelopment of the energy sensor concept[J]. Journal of Physiology, 2010, 574(1):7-15.
[29]孟胜喜,冯琴,彭景华,等. BZL方对游离脂肪酸诱导HepG2细胞脂肪沉积和LKB1-AMPK-ACC信号传导通路的影响[J].中华中医药杂志, 2014(5):1391-1396.
[30]匡霞,陆付耳,易屏.小檗碱对HepG2胰岛素抵抗细胞模型中LKB1-AMPK-TORC2信号网络的影响[J].中国中西医结合消化杂志, 2015(7):467-471.
[31]Li X, Li X, Chen H, et al. Non-esterified fatty acids activate the AMP-activated protein kinase signaling pathway to regulate lipid metabolism in bovine hepatocytes[J]. Cell Biochemistry&Biophysics, 2013, 67(3):1157-1169.
[32]Li X, Li Y, Ding H, et al. Insulin suppresses the AMPK signaling pathway toregulatelipidmetabolism inprimarycultured hepatocytes of dairy cows[J]. Journal of Dairy Research, 2018,(85):157-162.
[33]高晓娜,郭小权.一磷酸腺苷激活的蛋白激酶对动物糖脂代谢的调节作用[J].动物营养学报, 2017, 29(12):4287-4294.
[34]李琳,郑卓,贺红专. PPARγ基因调控猪脂肪沉积研究进展[J].中国猪业, 2016, 11(8):57-60.
[35]杜希良. miR-181a对犊牛原代肝细胞糖脂代谢稳态的调控机制[D].长春:吉林大学, 2016.
[36]Bellet MM, Nakahata Y, Boudjelal M, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1[J]. Proc Natil Acad Sci USA, 2013, 110(9):3333-3338.
[37]Liu L, Li X, Li Y, et al. Effects of nonesterified fatty acids on the synthesis and assembly of very low density lipoprotein in bovine hepatocytes in vitro[J]. Journal of Dairy Science, 2014, 97(3):1328-1335.
[38]Ito M, Nagasawa M, Omae N, et al. A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes[J]. Journal of Lipid Research, 2013, 54(6):1531-1540.
[39]Zhang M, Zhang S, Hui Q, et al.β-hydroxybutyrate facilitates fatty acids synthesis mediated by sterol regulatory element-binding protein1 in bovine mammary epithelial cells[J]. Cellular Physiology&Biochemistry, 2015, 37(6):2115-2124.
[40]Chau MD, Gao J, Yang Q, et al. Fibroblast growth factor 21regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway[J]. Proc Natil Acad Sci USA, 2010, 107(28):12553-12558.
[41]Li X, Chen H, Guan Y, et al. Acetic acid activates the AMPactivated protein kinase signal pathway to regulate lipid metabolism in bovine hepatocytes[J]. Journal of Steroid Biochemistry&Molecular Biology, 2013, 138(7):445-454.
[42]王怡,刘宗平.奶牛围产期脂肪代谢的研究进展[J].畜牧与兽医, 2013, 45(4):98-101.
[43]孙艳发,张敏,李焰,等.维生素E对动物脂肪代谢调控的研究进展[J].中国畜牧杂志, 2015, 51(13):82-85.
[44]Shi X, Li D, Deng Q, et al. Acetoacetic acid induces oxidative stress to inhibit the assembly of very low density lipoprotein in bovine hepatocytes[J]. Journal of Dairy Research, 2016, 83(4):442-446.
[45]Ono K, Horie T, Nishino T, et al. MicroRNA-33a/b in lipid metabolism-novel “thrifty” models[J]. Circulation Journal Official Journal of the Japanese Circulation Society, 2015, 79(2):278-284.
[46]靳青,魏晨,张相伦,等. miRNA-33对胆固醇合成的调控作用及其在肉牛上的研究进展[J].草食家畜, 2018(4):5-9.