自噬在奶牛乳腺炎、酮病、脂肪肝中的作用机制研究进展

doi:10.16431/j.cnki.1671-7236.2024.12.010

摘要/Abstract

摘要： 奶牛乳腺炎、酮病和脂肪肝都是奶牛的常见疾病，不仅严重危害了奶牛健康，还给奶牛业带来了巨大的经济损失。自噬是发生在真核生命中高度保守性的生命过程，能清除细胞内有害物质，保证内环境稳态，对生物体健康的维系具有重要意义。自噬激活的途径多种多样，既包括腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase，AMPK)和雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)等信号通路介导的溶酶体自噬，还包括由PTEN诱导的激酶1(PTEN-induced kinase 1，PINK1)/Parkin RBR E3泛素蛋白连接酶(Parkin RBR E3 ubiquitin protein ligase，PARK2)途径介导的线粒体自噬，此外，自噬的激活还与多种营养物质的调控有关，如植物提取物、氨基酸和维生素等。笔者阐述了自噬在奶牛乳腺炎、酮病和脂肪肝等常见疾病中通过线粒体或溶酶体途径发生反应并缓解上述疾病所造成负面影响的发生机制及研究进展，以期为奶牛生产中常见疾病的临床干预提供科学依据。

关键词: 自噬; 奶牛; 乳腺炎; 酮病; 脂肪肝

Abstract: Mastitis,ketosis and fatty liver are common diseases in dairy cows that not only severely harm their health but also cause significant economic losses to the dairy industry.Autophagy,a highly conserved process in eukaryotic life,helps clear harmful substances within cells,ensuring homeostasis and playing a crucial role in maintaining organismal health.There are various pathways for activating autophagy,including lysosomal autophagy mediated by AMPK and mTOR signaling pathways,as well as mitophagy mediated by the PINK1/PARK2 pathway.Additionally,autophagy activation is influenced by various nutrients,such as plant extracts,amino acids and vitamins.The authors discussed the mechanisms of autophagy in common diseases such as mastitis,ketosis and fatty liver in dairy cows,and reviewed recent research developments,aiming to provide a scientific basis for clinical interventions in common dairy cow diseases.

Key words: autophagy; dairy cows; mastitis; ketosis; fatty liver

中图分类号:

S852.21

张博, 耿阳, 李天尊, 敖英男, 卢宇来, 乌音嘎, 齐智利. 自噬在奶牛乳腺炎、酮病、脂肪肝中的作用机制研究进展[J]. 中国畜牧兽医, 2024, 51(12): 5218-5224.

ZHANG Bo, GENG Yang, LI Tianzun, AO Yingnan, LU Yulai, WU Yinga, QI Zhili. Research Progress on the Mechanisms of Autophagy in Mastitis,Ketosis and Fatty Liver in Dairy Cows[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(12): 5218-5224.

参考文献

[1] RAVANAN P, SRIKUMAR I F, TALWAR P.Autophagy:The spotlight for cellular stress responses[J].Life Sciences, 2017, 188:53-67.
[2] KIM K H, LEE M S.Autophagy—Key player in cellular and body metabolism[J].Nature Reviews Endocrinology, 2014, 10:322-337.
[3] ZHU C L, YAO R Q, LI L X, et al.Mechanism of mitophagy and its role in sepsis induced organ dysfunction:A review[J].Frontiers in Cell and Developmental Biology, 2021, 9:1498.
[4] MIZUSHIMA N, KOMATSU M.Autophagy:Renovation of cells and tissues[J].Cell, 2011, 147:728-741.
[5] CHU C T.Mechanisms of selective autophagy and mitophagy:Implications for neurodegenerative diseases[J].Neurobiology of Disease, 2019, 122:23-34.
[6] YIM W W Y, MIZUSHIMA N.Lysosome biology in autophagy[J].Cell Discovery, 2020, 6:6.
[7] LEE J Y, KOGA H, KAWAGUCHI Y, et al.HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy[J].The EMBO Journal, 2010, 29:969-980.
[8] CUERVO A M, WONG E.Chaperone-mediated autophagy:Roles in disease and aging[J].Cell Research, 2014, 24:92-104.
[9] WANG Y, ZHANG H.Regulation of autophagy by mTOR signaling pathway[J].Advances in Experimental Medicine and Biology, 2019, 1206:67-83.
[10] KHAMBU B, YAN S, HUDA N, et al.Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease[J].Liver Research, 2018, 9:4.
[11] PEÑA-MARTINEZ C, RICKMAN A D, HECKMANN B L.Beyond autophagy:LC3-associated phagocytosis and endocytosis[J].Science Advances, 2022, 8:n1702.
[12] KHAN S, DHAMA K, TIWARI R, et al.Advances in therapeutic and managemental approaches of bovine mastitis:A comprehensive review[J].Veterinary Quarterly, 2021, 41(1):107-136.
[13] HE W, MA S, LEI L.Prevalence, etiology, and economic impact of clinical mastitis on large dairy farms in China[J].Veterinary Microbiology, 2020, 242：108570.
[14] 王新慧.红景天苷对奶牛乳腺炎的调控作用及机制探究[D].武汉：华中农业大学, 2023.WANG X H.Investigation on the regulatory effect and mechanism of salidroside on dairy cow mastitis[D].Wuhan:Huazhong Agricultural University, 2023.(in Chinese)
[15] IDRISS S E, TAN AČG IN V, FOLT AY＇G S V, et al.Relationship between mastitis causative pathogens and somatic cell counts in dairy cows[J].Potravinarstvo, 2013, 7(1):207-212.
[16] 高红梅, 李云, 李玉卡, 等.奶牛临床型乳腺炎发生机制及其综合防治措施[J].今日畜牧兽医, 2020, 36:93-94.GAO H M, LI Y, LI Y K, et al.Mechanism of clinical mastitis in dairy cows and comprehensive prevention and control measures[J].Modern Animal Husbandry and Veterinary Medicine, 2020, 36:93-94.(in Chinese)
[17] 张博, 耿阳, 敖英男, 等.奶牛乳腺炎添加剂营养干预机制研究进展[J].中国奶牛, 2023，6:1-6.ZHANG B, GENG Y, AO Y N, et al.Research progress on nutritional intervention mechanism of dairy cow mastitis additives[J].China Dairy Cattle, 2023, 6:1-6.(in Chinese)
[18] ZHANG Y, CUI Y, WANG L, et al.Autophagy promotes osteoclast podosome disassembly and cell motility athrough the interaction of kindlin3 with LC3[J].Cellular Signalling, 2019, 67(7):109505.
[19] CAI J, LI J, ZHOU Y, et al.Staphylococcus aureus facilitates its survival in bovine macrophages by blocking autophagic flux[J].Journal of Cellular and Molecular Medicine, 2020, 24(6):3460-3468.
[20] GENG N, WANG X, YU X, et al.Staphylococcus aureus avoids autophagy clearance of bovine mammary epithelial cells by impairing lysosomal function[J].Frontiers in Immunology, 2020, 11:746.
[21] GUO W, LIU J, LI W, et al.Niacin alleviates dairy cow mastitis by regulating the GPR109A/AMPK/NRF2 signaling pathway[J].International Journal of Molecular Sciences, 2020, 21(9):3321.
[22] LIU S, GUO W, JIA Y, et al.Menthol targeting AMPK alleviates the inflammatory response of bovine mammary epithelial cells and restores the synthesis of milk fat and milk protein[J].Frontiers in Immunology, 2021，12：782989.
[23] WANG Z, LAN R, XU Y, et al.Taurine alleviates Streptococcus uberis-induced inflammation by activating autophagy in mammary epithelial cells[J].Frontiers in Immunology, 2021, 12:631113.
[24] ZHANG X, ZHANG H, GAO Y, et al.Forsythoside A regulates autophagy and apoptosis through the AMPK/mTOR/ULK1 pathway and alleviates inflammatory damage in MAC-T cells[J].International Immunopharmacology, 2023, 118:110053.
[25] LI Y, ZHU Y, CHU B, et al.Lactobacillus rhamnosus GR-1 prevents Escherichia coli-induced apoptosis through PINK1/Parkin-mediated mitophagy in bovine mastitis[J].Frontiers in Immunology, 2021:12, 715098.
[26] TAO L, LIU K, LI J, et al.Selenomethionine alleviates NF-κB-mediated inflammation in bovine mammary epithelial cells induced by Escherichia coli by enhancing autophagy[J].International Immunopharmacology, 2022, 110:108989.
[27] FIORE E, LISUZZO A, LAGHI L, et al.Serum metabolomics assessment of etiological processes predisposing ketosis in water buffalo during early lactation[J]. Journal of Dairy Science, 2023, 106(5):3465-3476.
[28] DUFFIELD T F, SANDALS D, LESLIE K E.Efficacy of monensin for the prevention of subclinical ketosis in lactating dairy cows[J].Journal of Dairy Science, 1998, 81(11):2866.
[29] ITLE A J, HUZZEY J M, WEARY D M, et al.Clinical ketosis and standing behavior in transition cows[J].Journal of Dairy Science, 2015, 98:128-134.
[30] PENG Z, LI X, WANG Z, et al.The effects of non-esterified fatty acids and β-hydroxybutyrate on the hepatic CYP2E1 in cows with clinical ketosis[J].The Journal of Dairy Research, 2019, 86(1):68-72.
[31] DUFFIELD T F, LISSEMORE K D, MCBRIDE B W, et al.Impact of hyperketonemia in early lactation dairy cows on health and production[J].Journal of Dairy Science, 2009, 92(2):571-580.
[32] LOIKLUNG C, SUKON P, THAMRONGYOSWITTAYAKUL C.Global prevalence of subclinical ketosis in dairy cows:A systematic review and Meta-analysis[J].Research in Veterinary Science，2022, 144:66-76.
[33] ZHANG D, WANG W, SUN X, et al.AMPK regulates autophagy by phosphorylating BECN1 at threonine 388[J].Autophagy, 2016, 12:1447-1459.
[34] DIKIC I, ELAZAR Z.Mechanism and medical implications of mammalian autophagy[J].Nature Reviews Molecular Cell Biology, 2018, 19:349-364.
[35] LI X, LI G, DU X, et al.Increased autophagy mediates the adaptive mechanism of the mammary gland in dairy cows with hyperketonemia[J].Journal of Dairy Science, 2020, 103(3):2545-2555.
[36] SINHA R A, FARAH B L, SINGH B K, et al.Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice[J].Hepatology, 2014, 59:1366-1380.
[37] XU Q, FAN Y, LOOR J J, et al.Adenosine 5'-monophosphate-activated protein kinase ameliorates bovine adipocyte oxidative stress by inducing antioxidant responses and autophagy[J].Journal of Dairy Science, 2021, 104(4):4516-4528.
[38] YU H, FAN M, CHEN X, et al.Activated autophagy-lysosomal pathway in dairy cows with hyperketonemia is associated with lipolysis of adipose tissues[J].Journal of Dairy Science, 2022, 105(8):6997-7010.
[39] XU Q, FAN Y, MAUCK J, et al.Role of diacylglycerol O-acyltransferase 1(DGAT1) in lipolysis and autophagy of adipose tissue from ketotic dairy cows[J].Journal of Dairy Science, 2024, 107(7):5150-5161.
[40] ZAHRAZADEH M, RIASI A, FARHANGFAR H, et al.Effects of close-up body condition score and selenium-vitamin E injection on lactation performance, blood metabolites, and oxidative status in high-producing dairy cows[J].Journal of Dairy Science, 2018, 101(11):10495-10504.
[41] YUE K, PU X, LOOR J J, et al.Impaired autophagy aggravates oxidative stress in mammary gland of dairy cows with clinical ketosis[J].Journal of Dairy Science, 2022, 105(7):6030-6040.
[42] VINCOW E S, THOMAS R E, MERRIHEW G E, et al.Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective[J].Autophagy, 2019, 15:1592-1605.
[43] SHEN T, XU F, FANG Z, et al.Hepatic autophagy and mitophagy status in dairy cows with subclinical and clinical ketosis[J].Journal of Dairy Science, 2021, 104(4):4847-4857.
[44] ZHU Y, LIU G, DU X, et al.Expression patterns of hepatic genes involved in lipid metabolism in cows with subclinical or clinical ketosis[J].Journal of Dairy Science, 2019, 102(2):1725-1735.
[45] YANG Y, JIANG S, YANG J, et al.β-hydroxybutyrate impairs the directionality of migrating neutrophil through inhibiting the autophagy-dependent degradation of Cdc42 and Rac1 in ketotic cows[J].Journal of Dairy Science, 2023, 106(11):8005-8016.
[46] BOBE G, YOUNG J W, BEITZ D C.Invited review:Pathology, etiology, prevention, and treatment of fatty liver in dairy cows[J].Journal of Dairy Science, 2004, 87(10):3105-3124.
[47] RINGSEIS R, GESSNER D K, EDER K.Molecular insights into the mechanisms of liver-associated diseases in early-lactating dairy cows:Hypothetical role of endoplasmic reticulum stress[J].Journal of Animal Physiology and Animal Nutrition, 2015，99:626-645.
[48] LI P, LI X B, FU S X, et al.Alterations of fatty acid β-oxidation capability in the liver of ketotic cows[J].Journal of Dairy Science, 2012, 95(4):1759-1766.
[49] SONG Y, LI N, GU J, et al.β-hydroxybutyrate induces bovine hepatocyte apoptosis via an ROS-p38 signaling pathway[J].Journal of Dairy Science, 2016, 99(11):9184-9198.
[50] HE A, CHEN X, TAN M, et al.Acetyl-CoA derived from hepatic peroxisomal β-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation[J]. Molecular Cell, 2020, 79:30-42.
[51] DING H, GE G, TSENG Y, et al.Hepatic autophagy fluctuates during the development of non-alcoholic fatty liver disease[J].Annals of Hepatology, 2020, 19:516-522.
[52] YANG L, LI P, FU S, et al.Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance[J].Cell Metabolism, 2010, 11:467-478.
[53] CHEN M, LOOR J J, ZHAI Q, et al.Short communication:Enhanced autophagy activity in liver tissue of dairy cows with mild fatty liver[J].Journal of Dairy Science, 2020, 103(4):3628-3635.
[54] DU X, LIU G, LOOR J J, et al.Impaired hepatic autophagic activity in dairy cows with severe fatty liver is associated with inflammation and reduced liver function[J].Journal of Dairy Science, 2018, 101(12):11175-11185.
[55] DU X, CHEN M, FANG Z, et al.Evaluation of hepatic AMP-activated protein kinase (AMPK), mechanistic target of rapamycin kinase complex 1(mTORC1) and autophagy-lysosomal pathway in cows with mild or moderate fatty liver[J].Journal of Dairy Science, 2024, 107(5):3269-3279.
[56] DONG J, YUE K, LOOR J J, et al.Increased adipose tissue lipolysis in dairy cows with fatty liver is associated with enhanced autophagy activity[J].Journal of Dairy Science, 2022, 105(2):1731-1742.
[57] ZHAO C, WU B, LI J, et al.AdipoRon alleviates fatty acid-induced lipid accumulation and mitochondrial dysfunction in bovine hepatocytes by promoting autophagy[J].Journal of Dairy Science, 2023, 106(8):5763-5774.
[58] 李胜开, 刘雨琪, 叶添梅, 等.过瘤胃胆碱在围产期奶牛的应用研究进展[J].乳业科学与技术, 2015, 38(6):27-30.LI S K, LIU Y Q, YE T M, et al.Research progress on the application of rumen choline in perinatal dairy cows[J].Dairy Science and Technology, 2015, 38(6):27-30.(in Chinese)
[59] ARSHAD U, HUSNAIN A, POINDEXTER M B, et al.Effect of source and amount of rumen-protected choline on hepatic metabolism during induction of fatty liver in dairy cows[J].Journal of Dairy Science, 2023, 106(10):6860-6879.
[60] PENG Z, ZHAO C, DU X, et al.Autophagy induced by palmitic acid regulates neutrophil adhesion through the granule-dependent degradation of αMβ2 integrin in dairy cows with fatty liver[J].Frontiers in Immunology, 2021, 12:726829.