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High levels of fatty acids inhibit β-casein synthesis through suppression of the JAK2/STAT5 and mTOR signaling pathways in mammary epithelial cells of cows with clinical ketosis

Published online by Cambridge University Press:  20 April 2020

Xin Shu ,
Zhiyuan Fang ,
Yuan Guan ,
Xiying Chen ,
Juan J. Loor ,
Hongdou Jia ,
Jihong Dong ,
Yazhe Wang ,
Rankun Zuo  and
Guowen Liu
...Show all authors
Xin Shu
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Zhiyuan Fang
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Yuan Guan
Affiliation:
College of Animal Science, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Xiying Chen
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Juan J. Loor
Affiliation:
Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Champaign, IL, USA
Hongdou Jia
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Jihong Dong
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Yazhe Wang
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Rankun Zuo
Affiliation:
College of Veterinary Medicine, Qingdao Agriculture University, Qingdao, Shandong, China
Guowen Liu
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Xiaobing Li
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
Xinwei Li*
Affiliation:
Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China
*
Author for correspondence: Xinwei Li, Email: [email protected]
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Abstract

Ketosis is a metabolic disease of dairy cows often characterized by high concentrations of ketone bodies and fatty acids, but low milk protein and milk production. The Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) and the mechanistic target of rapamycin (mTOR) signaling pathways are central for the regulation of milk protein synthesis. The effect of high levels of fatty acids on these pathways and β-casein synthesis are unknown in dairy cows with clinical ketosis. Mammary gland tissue and blood samples were collected from healthy (n = 15) and clinically-ketotic (n = 15) cows. In addition, bovine mammary epithelial cells (BMEC) were treated with fatty acids, methionine (Met) or prolactin (PRL), respectively. In vivo, the serum concentration of fatty acids was greater (P > 0.05) and the percentage of milk protein (P > 0.05) was lower in cows with clinical ketosis. The JAK2-STAT5 and mTOR signaling pathways were inhibited and the abundance of β-casein was lower in mammary tissue of cows with clinical ketosis (P > 0.05). In vitro, high levels of fatty acids inhibited the JAK2-STAT5 and mTOR signaling pathways (P > 0.05) and further decreased the β-casein synthesis (P > 0.05) in BMEC. Methionine or PRL treatment, as positive regulators, activated the JAK2-STAT5 and mTOR signaling pathways to increase the β-casein synthesis. Importantly, the high concentration of fatty acids attenuated the positive effect of Met or PRL on mTOR, JAK2-STAT5 pathways and the abundance of β-casein (P > 0.05). Overall, these data indicate that the high concentrations of fatty acids that reach the mammary cells during clinical ketosis inhibit mTOR and JAK2-STAT5 signaling pathways, and further suppress β-casein synthesis.

Keywords

Bovine mammary epithelial cellsdairy cowsfatty acidsmilk protein synthesis
Type
Research Article
Information
Journal of Dairy Research , Volume 87 , Issue 2 , May 2020 , pp. 212 - 219
Copyright
© The Author(s), 2020. Published by Cambridge University Press on behalf of Hannah Dairy Research Foundation.

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Footnotes

*

These authors contributed equally to this study.

References

Arriola Apelo, SI, Singer, LM, Lin, XY, McGilliard, ML, St-Pierre, NR and Hanigan, MD (2014) Isoleucine, leucine, methionine, and threonine effects on mammalian target of rapamycin signaling in mammary tissue. Journal of Dairy Science 97, 1047–1056.10.3168/jds.2013-7348CrossRefGoogle ScholarPubMed
Bionaz, M and Loor, JJ (2008) Gene networks driving bovine milk fat synthesis during the lactation cycle. BMC Genomics 9, 366.10.1186/1471-2164-9-366CrossRefGoogle ScholarPubMed
Bionaz, M and Loor, JJ (2011) Gene networks driving bovine mammary protein synthesis during the lactation cycle. Bioinformatics and Biology Insights 5, 83–98.10.4137/BBI.S7003CrossRefGoogle ScholarPubMed
Boutinaud, M, Guinard-Flament, J and Jammes, H (2004) The number and activity of mammary epithelial cells, determining factors for milk production. Reproduction Nutrition Development 44, 499–508.10.1051/rnd:2004054CrossRefGoogle ScholarPubMed
Burgos, SA, Kim, JJ, Dai, M and Cant, JP (2013) Energy depletion of bovine mammary epithelial cells activates AMPK and suppresses protein synthesis through inhibition of mTORC1 signaling. Hormone and Metabolic Research 45, 183–189.Google ScholarPubMed
Chiang, GG and Abraham, RT (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. Journal of Biological Chemistry 280, 25485–25490.10.1074/jbc.M501707200CrossRefGoogle ScholarPubMed
Davies, DT and Law Andrew, JR (1983) Variation in the protein composition of bovine casein micelles and serum casein in relation to micellar size and milk temperature. Journal of Dairy Research 50, 67–75.10.1017/S0022029900032532CrossRefGoogle Scholar
Duffield, TF, Lissemore, KD, McBride, BW and Leslie, KE (2009) Impact of hyperketonemia in early lactation dairy cows on health and production. Journal of Dairy Science 92, 571–580.10.3168/jds.2008-1507CrossRefGoogle Scholar
Gao, HN, Zhao, SG, Zheng, N, Zhang, YD, Wang, SS, Zhou, XQ and Wang, JQ (2017) Combination of histidine, lysine, methionine, and leucine promotes β-casein synthesis via the mechanistic target of rapamycin signaling pathway in bovine mammary epithelial cells. Journal of Dairy Science 100, 7696–7709.10.3168/jds.2015-10729CrossRefGoogle ScholarPubMed
Glascock, RF and Welch, VA (1974) Contribution of the fatty acids of three low density serum lipoproteins to bovine milk fat. Journal of Dairy Science 57, 1364–1370.10.3168/jds.S0022-0302(74)85068-XCrossRefGoogle ScholarPubMed
Hennighausen, L, Robinson, GW, Wagner, KU and Liu, W (1997) Prolactin signaling in mammary gland development. Journal of Biological Chemistry 272, 7567–7569.10.1074/jbc.272.12.7567CrossRefGoogle ScholarPubMed
Imada, K and Leonard, WJ (2000) The Jak-STAT pathway. Molecular Immunology 37, 1–11.10.1016/S0161-5890(00)00018-3CrossRefGoogle ScholarPubMed
Ingvartsen, KL (2006) Feeding- and management-related diseases in the transition cow: physiological adaptations around calving and strategies to reduce feeding-related diseases. Animal Feed Science and Technology 126, 175–213.10.1016/j.anifeedsci.2005.08.003CrossRefGoogle Scholar
Jiang, N, Wang, Y, Yu, Z, Hu, L, Liu, C, Gao, X and Zheng, S (2015) WISP3 (CCN6) regulates milk protein synthesis and cell growth through mTOR signaling in dairy cow mammary epithelial cells. DNA and Cell Biology 34, 524–533.10.1089/dna.2015.2829CrossRefGoogle ScholarPubMed
Kayano, M and Kataoka, T (2015) Screening for ketosis using multiple logistic regression based on milk yield and composition. Journal of Veterinary Medical Science 77, 1473–1478.10.1292/jvms.14-0691CrossRefGoogle ScholarPubMed
Kim, E (2009) Mechanisms of amino acid sensing in mTOR signaling pathway. Nutrition Research and Practice 3, 64–71.10.4162/nrp.2009.3.1.64CrossRefGoogle ScholarPubMed
Li, X, Li, X, Bai, G, Chen, H, Deng, Q, Liu, Z, Zhang, L, Liu, G and Wang, Z (2012) Effects of non-esterified fatty acids on the gluconeogenesis in bovine hepatocytes. Molecular and Cellular Biochemistry 359, 385–388.10.1007/s11010-011-1032-xCrossRefGoogle ScholarPubMed
Littledike, ET, Young, JW and Beitz, DC (1981) Common metabolic diseases of cattle: ketosis, milk fever, grass tetany, and downer cow complex. Journal of Dairy Science 64, 1465–1482.10.3168/jds.S0022-0302(81)82715-4CrossRefGoogle ScholarPubMed
Lu, LM, Gao, XJ, Li, QZ, Huang, JG, Liu, R and Li, HM (2012) Comparative phosphoproteomics analysis of the effects of L-methionine on dairy cow mammary epithelial cells. Canadian Journal of Animal Science 92, 433–442.10.4141/cjas2012-063CrossRefGoogle Scholar
Oetzel, GR (2004) Monitoring and testing dairy herds for metabolic disease. Veterinary Clinics of North America: Food Animal Practice 20, 651–674.Google ScholarPubMed
Ospina, PA, Nydam, DV, Stokol, T and Overton, TR (2010) Associations of elevated nonesterified fatty acids and β-hydroxybutyrate concentrations with early lactation reproductive performance and milk production in transition dairy cattle in the northeastern United States. Journal of Dairy Science 93, 1596–1603.10.3168/jds.2009-2852CrossRefGoogle ScholarPubMed
Palmquist, DL, Beaulieu, AD and Barbano, DM (1993) Feed and animal factors influencing milk fat composition. Journal of Dairy Science 76, 1753–1771.10.3168/jds.S0022-0302(93)77508-6CrossRefGoogle ScholarPubMed
Pauloin, A and Chanat, E (2012) Prolactin and epidermal growth factor stimulate adipophilin synthesis in HC11 mouse mammary epithelial cells via the PI3-kinase/Akt/mTOR pathway. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1823, 987–996.10.1016/j.bbamcr.2012.02.016CrossRefGoogle ScholarPubMed
Piechotta, M, Sander, AK, Kastelic, JP, Wilde, R, Heppelmann, M, Rudolphi, B, Schuberth, HJ, Bollwein, H and Kaske, M (2012) Short communication: prepartum plasma insulin-like growth factor-I concentrations based on day of insemination are lower in cows developing postpartum diseases. Journal of Dairy Science 95, 1367–1370.10.3168/jds.2011-4622CrossRefGoogle ScholarPubMed
Rezaei, R, Wu, Z, Hou, Y, Bazer, FW and Wu, G (2016) Amino acids and mammary gland development: nutritional implications for milk production and neonatal growth. Journal of Animal Science and Biotechnology 7, 20.10.1186/s40104-016-0078-8CrossRefGoogle ScholarPubMed
Sun, X, Wang, Y, Loor, JJ, Bucktrout, R, Shu, X, Jia, H, Dong, J, Zuo, R, Liu, G, Li, X and Li, X (2019) High expression of cell death-inducing DFFA-like effector a (CIDEA) promotes milk fat content in dairy cows with clinical ketosis. Journal of Dairy Science 102, 1682–1692.10.3168/jds.2018-15439CrossRefGoogle ScholarPubMed
Vanholder, T, Papen, J, Bemers, R, Vertenten, G and Berge, ACB (2015) Risk factors for subclinical and clinical ketosis and association with production parameters in dairy cows in the Netherlands. Journal of Dairy Science 98, 880–888.10.3168/jds.2014-8362CrossRefGoogle ScholarPubMed
Wang, X and Proud C, G (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21, 362–369.Google ScholarPubMed
Wang, M, Xu, B, Wang, H, Bu, D, Wang, J and Loor, JJ (2014) Effects of arginine concentration on the in vitro expression of casein and mTOR pathway related genes in mammary epithelial cells from dairy cattle. PLoS One 9, e95985.10.1371/journal.pone.0095985CrossRefGoogle ScholarPubMed
Wang, Y, Liu, J, Wu, H, Fang, X, Chen, H and Zhang, C (2017) Amino acids regulate mTOR pathway and milk protein synthesis in a mouse mammary epithelial cell line is partly mediated by T1R1/T1R3. European Journal of Nutrition 56, 2467–2474.10.1007/s00394-016-1282-1CrossRefGoogle Scholar
Yamashita, H, Nevalainen, MT, Xu, J, LeBaron, MJ, Wagner, KU, Erwin, RA and Rui, H (2001) Role of serine phosphorylation of Stat5a in prolactin-stimulated β-casein gene expression. Molecular and Cellular Endocrinology 183, 151–163.10.1016/S0303-7207(01)00546-9CrossRefGoogle ScholarPubMed
Yamdagni, S and Schultz, LH (1970) Fatty acid composition of blood plasma lipids of normal and ketotic cows. Journal of Dairy Science 53, 1046–1050.10.3168/jds.S0022-0302(70)86343-3CrossRefGoogle ScholarPubMed
Yang, J, Kennelly, JJ and Baracos, VE (2000) The activity of transcription factor Stat5 responds to prolactin, growth hormone, and IGF-I in rat and bovine mammary explant culture. Journal of Animal Science 78, 3114–3125.10.2527/2000.78123114xCrossRefGoogle ScholarPubMed
Yang, J, Hong, C, Xu, Q, Zhao, F, Liu, J and Liu, H (2015) Methionyl-methionine promotes a-s1 casein synthesis in bovine mammary gland explants by enhancing intracellular substrate availability and activating JAK2-STAT5 and mTOR-mediated signaling pathways. Journal of Nutrition 145, 1748–1753.10.3945/jn.114.208330CrossRefGoogle Scholar
Zhang, M, Zhao, S, Wang, S, Luo, C, Gao, H, Zheng, N and Wang, J (2018) D-Glucose and amino acid deficiency inhibits casein synthesis through JAK2/STAT5 and AMPK/mTOR signaling pathways in mammary epithelial cells of dairy cows. Journal of Dairy Science 101, 1737–1746.CrossRefGoogle ScholarPubMed
Zhang, B, Guo, H, Yang, W, Li, M, Zou, Y, Loor, JJ, Xia, C and Xu, C (2019 a) Effects of ORAI calcium release-activated calcium modulator 1 (ORAI1) on neutrophil activity in dairy cows with subclinical hypocalcemia1. Journal of Animal Science 97, 3326–3336.10.1093/jas/skz209CrossRefGoogle ScholarPubMed
Zhang, S, Qi, H, Wen, XP, Li, P, Gao, XJ and Ao, JX (2019 b) The phosphorylation of Tudor-SN mediated by JNK is involved in the regulation of milk protein synthesis induced by prolactin in BMECs. Journal of Cellular Physiology 234, 6077–6090.10.1002/jcp.27343CrossRefGoogle ScholarPubMed
Zhou, Y, Zhou, Z, Peng, J and Loor, JJ (2018) Methionine and valine activate the mammalian target of rapamycin complex 1 pathway through heterodimeric amino acid taste receptor (TAS1R1/TAS1R3) and intracellular Ca2+ in bovine mammary epithelial cells. Journal of Dairy Science 101, 11354–11363.10.3168/jds.2018-14461CrossRefGoogle ScholarPubMed
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