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Ketosis Under a Systems Veterinary Medicine Perspective

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Periparturient Diseases of Dairy Cows

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Abstract

Ketosis (hyperketonemia) is a prevalent metabolic disease of transition dairy cows that affects ~30–40% of the cows during early lactation. Cows with ketosis have lower milk yield and reproductive performance, greater risk of other periparturient diseases, and higher culling rates. Ketosis is characterized by an excess level of circulating ketone bodies with blood concentration of beta-hydroxybutyrate (BHBA) been recognized as a golden standard for diagnosis of the disease. However, the cutoff value for serum BHBA for diagnosis of ketosis appears to be somewhat arbitrary. Negative energy balance at early lactation is the primary hypothesis for the explanation of the pathobiology of ketosis. Treatment strategies are focused on maintenance of glucose and ketone body homeostasis. The exact causes and the etiopathology of ketosis remain incompletely understood. In some recent metabolomics studies, data show that the number of metabolites altered in the plasma/serum or milk and metabolic pathways perturbed during ketosis are numerous. It is obvious that ketone bodies and glucose metabolism are not the only perturbed metabolites during ketosis. Mounting evidence indicates that multiple alterations also occur at proteome, transcriptome, and genome levels and other component networks. Integration of all the knowledge generated by genomics, transcriptomics, proteomics, metabolomics, and lipidomics can help detect perturbations of biological information on distinct tiers and give insight on the causes and pathobiology of ketosis in dairy cows.

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References

  • Akbar H, Batistel F, Drackley JK et al (2015) Alterations in hepatic FGF21, co-regulated genes, and upstream metabolic genes in response to nutrition, ketosis and inflammation in peripartal Holstein cows. PLoS One 10:e0139963

    Article  PubMed  PubMed Central  Google Scholar 

  • Badman MK, Pissios P, Kennedy AR et al (2007) Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic States. Cell Metab 5:426–437

    Article  CAS  PubMed  Google Scholar 

  • Baes M, Van Veldhoven PP (2012) Mouse models for peroxisome biogenesis defects and β-oxidation enzyme deficiencies. Biochim Biophys Acta 1822:1489–1500

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Hoo RL, Konishi M et al (2011) Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 286:34559–34566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dann HM, Drackley JK (2005) Carnitine palmitoyltransferase I in liver of periparturient dairy cows: Effects of prepartum intake, postpartum induction of ketosis, and periparturient disorders. J Dairy Sci 88:3851–3859

    Article  CAS  PubMed  Google Scholar 

  • D’Mello JPF (2003) Amino acids as multifunctional molecules. In: D’Mello JPF (ed) Amino acids in animal nutrition, 2nd edn. CABI Publishing, Oxfordshire, pp 1–14

    Chapter  Google Scholar 

  • Duffield TF (2000) Subclinical ketosis in lactating dairy cattle. Vet Clin North Am Food Anim Pract 16:231–253

    Article  CAS  PubMed  Google Scholar 

  • Duffield TF, Lissemore KD, McBride BW et al (2009) Impact of hyperketonemia in early lactation dairy cows on health and production. J Dairy Sci 92:571–580

    Article  CAS  PubMed  Google Scholar 

  • Ferreira G, Weiss WP, Willett LB (2007) Changes in measures of biotin status do not reflect milk yield responses when dairy cows are fed supplemental biotin. J Dairy Sci 90:1452–1459

    Article  CAS  PubMed  Google Scholar 

  • Gao H, Dong B, Liu X (2008) Metabonomic profiling of renal cell carcinoma: High-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis. Anal Chim Acta 624:269–277

    Article  CAS  PubMed  Google Scholar 

  • Gälman C, Lundåsen T, Kharitonenkov A et al (2008) The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab 8:169–174

    Article  PubMed  Google Scholar 

  • Gordon JL, LeBlanc SJ, Duffield TF (2013) Ketosis treatment in lactating dairy cattle. Vet Clin North Am Food Anim Pract 29:433–445

    Article  PubMed  Google Scholar 

  • Hamana M, Ohtsuka H, Oikawa M et al (2010) Blood free amino acids in the postpartum dairy cattle with left displaced abomasums. J Vet Med Sci 72:1355–1358

    Article  CAS  PubMed  Google Scholar 

  • Herdt TH (2000) Ruminant adaptation to negative energy balance - Influences on the etiology of ketosis and fatty liver. Vet Clin North Am Food Anim Pract 16:215–230

    Article  CAS  PubMed  Google Scholar 

  • Heringstad B, Chang YM, Gianola D et al (2005) Genetic analysis of clinical mastitis, milk fever, ketosis, and retained placenta in three lactations of Norwegian Red Cows. J Dairy Sci 88:3273–3281

    Article  CAS  PubMed  Google Scholar 

  • Hinko CN, Crider AM, Kliem MA et al (1996) Anticonvulsant activity of novel derivatives of 2- and 3-piperidinecarboxylic acid in mice and rats. Neuropharmacology 35:1721–1735

    Article  CAS  PubMed  Google Scholar 

  • Holtenius P, Holtenius K (1996) New aspects of ketone bodies in energy metabolism of dairy cows: a review. Zentralbl Veterinarmed A 43:579–587

    Article  CAS  PubMed  Google Scholar 

  • Kadarmideen HN, Thompson R, Simm G (2000) Linear and threshold model genetic parameters for disease, fertility and milk production in dairy cattle. Anim Sci 71:411–419

    Article  Google Scholar 

  • Kharitonenkov A, Shiyanova TL, Koester A et al (2005) FGF-21 as a novel metabolic regulator. J Clin Invest 115:1627–1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein MS, Almstetter MF, Schlamberger G et al (2010) Nuclear magnetic resonance and mass spectrometry-based milk metabolomics in dairy cows during early and late lactation. J Dairy Sci 93:1539–1550

    Article  CAS  PubMed  Google Scholar 

  • Klein MS, Buttchereit N, Sebastian P et al (2012) NMR metabolomic analysis of dairy cows reveals milk glycerophosphocholine to phosphocholine ratio as prognostic biomarker for risk of ketosis. J Proteome Res 11:1373–1381

    Article  CAS  PubMed  Google Scholar 

  • Kuhla B, Albrecht D, Kuhla S et al (2009) Proteome analysis of fatty liver in feed-deprived dairy cows reveals interaction of fuel sensing, calcium, fatty acid, and glycogen metabolism. Physiol Genomics 37:88–98

    Article  CAS  PubMed  Google Scholar 

  • Lecker SH, Goldgerger AL, Mitch WE (2006) Protein degradation by the ubiquitin–proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819

    Article  CAS  PubMed  Google Scholar 

  • Li P, Lin Y, Li D et al (2007) Amino acids and immune function. Br J Nutr 98:237–352

    Article  CAS  PubMed  Google Scholar 

  • Li P, Li XB, Fu SX et al (2012) Alterations of fatty acid β-oxidation capability in the liver of ketotic cows. J Dairy Sci 95:1759–1766

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Xu C, Xia C et al (2014) Plasma metabolic profiling of dairy cows affected with clinical ketosis using LC/MS technology. Vet Q 34:152–158

    Article  CAS  PubMed  Google Scholar 

  • Loor JJ, Everts RE, Bionaz M et al (2007) Nutrition-induced ketosis alters metabolic and signaling gene networks in liver of periparturient dairy cows. Physiol Genomics 32:105–116

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Antunes Fernandes E, Páez Cano AE et al (2013) Changes in milk proteome and metabolome associated with dry period length, energy balance, and lactation stage in postparturient dairy cows. J Proteome Res 12:3288–3296

    Article  CAS  PubMed  Google Scholar 

  • Mahendran Y, Vangipurapu J, Cedergerg H et al (2013) Association of ketone body levels with hyperglycemia and type 2 diabetes in 9,398 Finnish men. Diabetes 62:3618–3626

    Google Scholar 

  • Marsh DC, Vreugdenhil PK, Mack VE et al (1993) Glycine protects hepatocytes from injury caused by anoxia, cold ischemia and mitochondrial inhibitors, but not injury caused by calcium ionophores or oxidative stress. Hepatology 17:91–98

    Google Scholar 

  • Marvin DA, Francis B (1949) A metabolic study of α-aminobutyric acid. J Biol Chem 180:1059–1063

    Google Scholar 

  • Mitch WE, Goldberg AL (1996) Mechanisms of muscle wasting: the role of the ubiquitin-proteasome system. N Engl J Med 335:1897–1905

    Article  CAS  PubMed  Google Scholar 

  • Moriwaki H, Miwa Y, Tajika M et al (2004) Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 313:405–409

    Article  CAS  PubMed  Google Scholar 

  • Motyl T, Barej W (1986) Plasma amino acid indices and urinary 3-methyl histidine excretion in dairy cows in early lactation. Ann Rech Vet 17:153–157

    CAS  PubMed  Google Scholar 

  • Munro IC, Berndt WO, Borzelleca JF et al (1998) Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data. Food Chem Toxicol 36:1139–1174

    Article  CAS  PubMed  Google Scholar 

  • Murondoti A, Jorritsma R, Beynen AC et al (2004) Unrestricted feed intake during the dry period impairs the postpartum oxidation and synthesis of fatty acids in the liver of dairy cows. J Dairy Sci 87:672–679

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa-Ueta H, Katoh N (2000) Reduction in serum lecithin: cholesterol acyltransferase activity prior to the occurrence of ketosis and milk fever in cows. J Vet Med Sci 62:1263–1267

    Article  CAS  PubMed  Google Scholar 

  • Ness GC, Chambers CM (2000) Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 224:8–19

    Article  CAS  PubMed  Google Scholar 

  • Oetzel GR (2007) Herd-level ketosis—diagnosis and risk factors. Paper presented at the 40th Annual Conference—American Association of Bovine Practitioners, Vancouver, BC, Canada, 19 September 2007

    Google Scholar 

  • Oetzel GR (2013) Understanding the impact of subclinical ketosis. Paper presented at the 24th Florida Ruminant Nutrition Symposium, University of Florida, Gainesville, 5–6 February 2013

    Google Scholar 

  • Oikawa S, Katoh N, Kawawa F et al (1997) Decreased serum apolipoprotein B-100 and A-I concentrations in cows with ketosis and left displacement of the abomasums. Am J Vet Res 58:121–125

    CAS  PubMed  Google Scholar 

  • Okuda T, Morita N (2012) A very low carbohydrate ketogenic diet prevents the progression of hepatic steatosis caused by hyperglycemia in a juvenile obese mouse model. Nutr Diabetes 2:e50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ospina PA, Nydam DV, Stokol T et al (2010) Evaluation of nonesterified fatty acids and beta-hydroxybutyrate in transition dairy cattle in the northeastern United States: Critical thresholds for prediction of clinical diseases. J Dairy Sci 93:546–554

    Article  CAS  PubMed  Google Scholar 

  • Pasquale MGD (2007) Energy metabolism. In: Amino acids and proteins for the athlete: the anabolic edge, 2nd edn. CRC Press, Boca Raton, pp 107–133

    Chapter  Google Scholar 

  • Petersen AK, Zeilinger S, Kastenmüller G et al (2014) Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits. Hum Mol Genet 23:534–545

    Article  CAS  PubMed  Google Scholar 

  • Postic C, Girard J (2008) The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab 34:643–648

    Article  CAS  PubMed  Google Scholar 

  • Rognstad R (1979) Rate-limiting steps in metabolic pathways. J Biol Chem 254:1875–1878

    CAS  PubMed  Google Scholar 

  • Salway JG (2004) Metabolism at a glance, 3rd edn. Wiley-Blackwell, Hoboken

    Google Scholar 

  • Scaglia N, Igal RA (2005) Stearoyl-CoA desaturase is involved in the control of proliferation, anchorage-independent growth, and survival in human transformed cells. J Biol Chem 280:25339–25349

    Article  CAS  PubMed  Google Scholar 

  • Schoenberg KM, Giesy SL, Harvatine KJ et al (2011) Plasma FGF21 is elevated by the intense lipid mobilization of lactation. Endocrinology 152:4652–4661

    Article  CAS  PubMed  Google Scholar 

  • Shaw JC (1956) Ketosis in dairy cattle. A review. J Dairy Sci 39:402–434

    Article  CAS  Google Scholar 

  • Shin SY, Fauman EB, Petersen AK et al (2014) An atlas of genetic influences on human blood metabolites. Nat Genet 46:543–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siddiqi NJ, Alhomida AS, Pandey VC (2002) Hydroxyproline distribution in the plasma of various mammals. J Biochem Mol Biol Biophys 6:159–163

    Article  CAS  PubMed  Google Scholar 

  • Sun LW, Zhang HY, Wu L et al (2014) 1H-Nuclear magnetic resonance-based plasma metabolic profiling of dairy cows with clinical and subclinical ketosis. J Dairy Sci 97:1552–1562

    Article  CAS  PubMed  Google Scholar 

  • Tetens J, Heuer C, Heyer I et al (2015) Polymorphisms within the APOBR gene are highly associated with milk levels of prognostic ketosis biomarkers in dairy cows. Physiol Genomics 47:129–137

    Article  CAS  PubMed  Google Scholar 

  • Tveit B, Lingass F, Svendsen M et al (1992) Etiology of acetonemia in Norwegian cattle. 1. Effect of ketogenic silage, season, energy level, and genetic factors. J Dairy Sci 75:2421–2432

    Article  CAS  PubMed  Google Scholar 

  • Uribe HA, Kennedy BW, Martin SW et al (1995) Genetic parameters for common health disorders of Holstein cows. J Dairy Sci 78:421–430

    Article  CAS  PubMed  Google Scholar 

  • Watanabe M, Maemura K, Kanbara K et al (2002) GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol 213:1–47

    Article  CAS  PubMed  Google Scholar 

  • Xie L, Innis SM (2008) Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation. J Nutr 138:2222–2228

    Article  CAS  PubMed  Google Scholar 

  • Xu C, Wang Z (2008) Comparative proteomic analysis of livers from ketotic cows. Vet Res Commun 32:263–273

    Article  PubMed  Google Scholar 

  • Xu C, Wang Z, Liu G et al (2008) Metabolic characteristic of the liver of dairy cows during ketosis based on comparative proteomics. Asian-Australas J Anim Sci 21:1003–1010

    Article  CAS  Google Scholar 

  • Xu C, Shu S, Xia C et al (2014) Investigation on the relationship of insulin resistance and ketosis in dairy cows. J Vet Sci Technol 5:162

    Google Scholar 

  • Xu C, Shu S, Xia C et al (2015b) Mass spectral analysis of urine proteomic profiles of dairy cows suffering from clinical ketosis. Vet Q 35:133–141

    Article  PubMed  Google Scholar 

  • Xu C, Li Y, Xia C et al (2015a) 1H NMR-based plasma metabolic profiling of dairy cows with Type I and Type II ketosis. Pharm Anal Acta 6:1000328

    Google Scholar 

  • Xu C, Xu Q, Chen Y et al (2016b) FGF-21: promising biomarker for detecting ketosis in dairy cows. Vet Res Commun 40:49–54

    Article  PubMed  Google Scholar 

  • Xu C, Sun LW, Xia C et al (2016a) 1H-nuclear magnetic resonance-based plasma metabolic profiling of dairy cows with fatty liver. Asian-Australas J Anim Sci 29:219–229

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto M, Nakagawa-Ueta H, Katoh N et al (2001) Decreased concentration of serum apolipoprotein C-III in cows with fatty liver, ketosis, left displacement of the abomasum, milk fever and retained placenta. J Vet Med Sci 63:227–231

    Article  CAS  PubMed  Google Scholar 

  • Zierer J, Menni C, Kastenmüller G et al (2015) Integration of ‘omics’ data in aging research: from biomarkers to systems biology. Aging Cell 14:933–944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang G, Hailemariam D, Dervishi E et al (2016) Dairy cows affected by ketosis show alterations in innate immunity and lipid and carbohydrate metabolism during the dry off period and postpartum. Res Vet Sci 107:249–256

    Google Scholar 

  • Zhang G, Dervishi E, Dunn SM et al (2017a) Metabotyping reveals distinct metabolic alterations in ketotic cows and identifies early predictive serum biomarkers for the risk of disease. Metabolomics 13:43

    Google Scholar 

  • Zhang G, Dervishi E, Mandal R et al (2017b) Metallotyping of ketotic dairy cows reveals major alterations preceding, associating, and following the disease occurrence. Metabolomics 13:97

    Google Scholar 

  • Zhang H, Wu L, Xu C et al (2013) Plasma metabolomic profiling of dairy cow affected with ketosis using gas chromatography mass spectrometry. BMC Vet Res 9:186

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Liu G, Wang H et al (2012) Detection of subclinical ketosis in dairy cows. Pak Vet J 32:156–151

    Google Scholar 

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Authors and Affiliations

  1. Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada

    Guanshi Zhang D.V.M., Ph.D. & Burim N. Ametaj D.V.M., Ph.D., Ph.D.

  2. Center for Renal Translational Medicine, School of Medicine, Institute of Metabolomic Medicine, University of California, La Jolla, San Diego, CA, 92093, USA

    Guanshi Zhang D.V.M., Ph.D.

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  1. Guanshi Zhang D.V.M., Ph.D.
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  2. Burim N. Ametaj D.V.M., Ph.D., Ph.D.
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Correspondence to Guanshi Zhang D.V.M., Ph.D. .

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  1. Department of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada

    Burim N. Ametaj

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Zhang, G., Ametaj, B.N. (2017). Ketosis Under a Systems Veterinary Medicine Perspective. In: Ametaj, B. (eds) Periparturient Diseases of Dairy Cows. Springer, Cham. https://doi.org/10.1007/978-3-319-43033-1_10

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