Lactoferrin as a promising remedy for metabolic syndrome therapy: from molecular mechanisms to clinical trials

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The review summarizes data on the effect of the protein present in exocrine secretions and neutrophils, lactoferrin, on components of metabolic syndrome pathogenesis. The molecular mechanisms of lactoferrin participation in the regulation of carbohydrate and lipid metabolism, such as that of lipoproteins, glycated proteins, fatty and bile acids, are contemplated. The influence of lactoferrin on the development of insulin resistance and hypertension, on proliferation of adipocytes, on inflammatory processes and endocrine control is considered. An analysis of population-based studies on the link between lactoferrin gene expression level and metabolic syndrome evidences is carried out. The results of numerous experiments focused on the effects of lactoferrin in metabolic syndrome and obesity animal models are presented. The results of the first international clinical trials aimed to correct obesity and type 2 diabetes mellitus in volunteers are discussed.

Anna Yu. Elizarova

Institute of Experimental Medicine

Author for correspondence.
SPIN-code: 3059-4381

Russian Federation, Saint Petersburg

PhD student, Research fellow of the Department of Molecular Genetics

Valeria A. Kostevich

Institute of Experimental Medicine; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

ORCID iD: 0000-0002-1405-1322
SPIN-code: 2726-2921

Russian Federation, Saint Petersburg; Moscow

PhD (Biology), Senior Researcher of the Department of Molecular Genetics; Research fellow of the Department of Biophysics

Irina V. Voynova

Institute of Experimental Medicine


Russian Federation, Saint Petersburg

PhD student, Research fellow of the Department of Molecular Genetics

Alexey V. Sokolov

Institute of Experimental Medicine; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency; Saint Petersburg State University

ORCID iD: 0000-0001-9033-0537
SPIN-code: 7427-7395

Russian Federation, Saint Petersburg; Moscow; Saint Petersburg

Doctor of Biological Sciences, Head of the Laboratory of Biochemical Genetics of the Department of Molecular Genetics; Senior Researcher of the Department of Biophysics; Professor of Chair of Fundamental Problems of Medicine and Medical Technology 

  1. Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis. 2017;11(8):215-225.
  2. Zhang X, Beynen AC. Lowering effect of dietary milk-whey protein v. casein on plasma and liver cholesterol concentrations in rats. Br J Nutr. 2007;70(01):139.
  3. McCrory C, Layte R. Breastfeeding and risk of overweight and obesity at nine-years of age. Soc Sci Med. 2012;75(2):323-330.
  4. Imai CM, Gunnarsdottir I, Thorisdottir B, et al. Associations between infant feeding practice prior to six months and body mass index at six years of age. Nutrients. 2014;6(4):1608-1617.
  5. Huang J, Zhang Z, Wu Y, et al. Early feeding of larger volumes of formula milk is associated with greater body weight or overweight in later infancy. Nutr J. 2018;17(1):12.
  6. Yan J, Liu L, Zhu Y, et al. The association between breastfeeding and childhood obesity: a meta-analysis. BMC Public Health. 2014;14:1267.
  7. Jensen RG. The lipids in human milk. Prog Lipid Res. 1996;35(1):53-92.
  8. Климов А.Н., Никуличева Н.Г. Обмен липидов и липопротеинов и его нарушения. – СПб.: Питер Ком, 1999. – 512 с. [Klimov AN, Nikulicheva NG. Obmen lipidov i lipoproteinov i ego narusheniya. Saint Petersburg: Piter Kom; 1999. 512 p. (In Russ.)]
  9. Huettinger M, Retzek H, Eder M, Goldenberg H. Characteristics of chylomicron remnant uptake into rat liver. Clin Biochem. 1988;21(2):87-92.
  10. Ziere GJ, Bijsterbosch MK, van Berkel TJ. Removal of 14 N-terminal amino acids of lactoferrin enhances its affinity for parenchymal liver cells and potentiates the inhibition of beta- very low density lipoprotein binding. J Biol Chem. 1993;268(36):27069-27075.
  11. Strickland DK, Ashcom JD, Williams S, et al. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem. 1990;265(29):17401-17404.
  12. Huettinger M, Retzek H, Hermann M, Goldenberg H. Lactoferrin specifically inhibits endocytosis of chylomicron remnants but not alpha-macroglobulin. J Biol Chem. 1992;267(26):18551-18557.
  13. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest. 2001;108(6):779-784.
  14. Meilinger M, Haumer M, Szakmary KA, et al. Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor-related protein/α 2-macroglobulin receptor and transport to endosomes. FEBS Lett. 1995;360(1):70-74.
  15. Dijk MCM, Ziere GJ, Berkel TJC. Characterization of the chylomicron-remnant-recognition sites on parenchymal and Kupffer cells of rat liver Selective inhibition of parenchymal cell recognition by lactoferrin. Eur J Biochem. 1992;205(2):775-784.
  16. Crawford SE, Borensztajn J. Plasma clearance and liver uptake of chylomicron remnants generated by hepatic lipase lipolysis: evidence for a lactoferrin-sensitive and apolipoprotein E-independent pathway. J Lipid Res. 1999;40(5):797-805.
  17. van Dijk MCM, Ziere GJ, Boers W, et al. Recognition of chylomicron remnants and β-migrating very-low-density lipoproteins by the remnant receptor of parenchymal liver cells is distinct from the liver α2-macroglobulin-recognition site. Biochem J. 1991;279(3):863-870.
  18. Ji ZS, Mahley RW. Lactoferrin binding to heparan sulfate proteoglycans and the LDL receptor-related protein. Further evidence supporting the importance of direct binding of remnant lipoproteins to HSPG. Arterioscler Thromb. 1994;14(12):2025-2031.
  19. Willnow TE, Goldstein JL, Orth K, et al. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992;267(36):26172-26180.
  20. Ono T, Morishita S, Fujisaki C, et al. Effects of pepsin and trypsin on the anti-adipogenic action of lactoferrin against pre-adipocytes derived from rat mesenteric fat. Br J Nutr. 2011;105(2):200-211.
  21. Hofmann SM, Zhou L, Perez-Tilve D, et al. Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Invest. 2007;117(11):3271-3282.
  22. Vassiliou G, Benoist F, Lau P, et al. The low density lipoprotein receptor-related protein contributes to selective uptake of high density lipoprotein cholesteryl esters by SW872 liposarcoma cells and primary human adipocytes. J Biol Chem. 2001;276(52):48823-48830.
  23. Brandl N, Zemann A, Kaupe I, et al. Signal transduction and metabolism in chondrocytes is modulated by lactoferrin. Osteoarthritis Cartilage. 2010;18(1):117-125.
  24. Grey A, Banovic T, Zhu Q, et al. The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells. Mol Endocrinol. 2004;18(9):2268-2278.
  25. Takeuchi T, Kitagawa H, Harada E. Evidence of lactoferrin transportation into blood circulation from intestine via lymphatic pathway in adult rats. Exp Physiol. 2004;89(3):263-270.
  26. Kajikawa M, Ohta T, Takase M, et al. Lactoferrin inhibits cholesterol accumulation in macrophages mediated by acetylated or oxidized low-density lipoproteins. Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism. 1994;1213(1):82-90.
  27. Костевич В.А., Соколов А.В., Захарова Е.Т., Васильев В.Б. Анализ содержания и насыщенности железом и медью лактоферрина в молоке у женщин с первого дня и до 5 лет лактации // Медицинский академический журнал. – 2014. – Т. 14. – № 1. – С. 80–86. [Kostevich VA, Sokolov AV, Zakharova ET, Vasil’ev VB. Analysis of lactoferrin concentration and iron/copper saturation in breast milk women from day 1 to 5 years of lactation. Med Acad J. 2014;14(1);80-86. (In Russ.)]
  28. Suginohara Y, Miyazaki A, Hakamata H, et al. The heparin-bound fraction of human lipoprotein-deficient serum inhibits endocytic uptake of oxidized low density lipoprotein by macrophages. Atherosclerosis. 1996;120(1-2):167-179.
  29. Schmidt AM, Vianna M, Gerlach M, et al. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem. 1992;267(21):14987-14997.
  30. Thornalley PJ. Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol (Noisy-le-grand). 1998;44(7):1013-1023.
  31. Shimizu H. Development of an enteric-coated lactoferrin tablet and its application. BioMetals. 2004;17(3):343-347.
  32. Takeuchi T, Shimizu H, Ando K, Harada E. Bovine lactoferrin reduces plasma triacylglycerol and NEFA accompanied by decreased hepatic cholesterol and triacylglycerol contents in rodents. Br J Nutr. 2004;91(4):533-538.
  33. Nakamura K, Morishita S, Ono T, et al. Lactoferrin interacts with bile acids and increases fecal cholesterol excretion in rats. Biochem Cell Biol. 2017;95(1):142-147.
  34. McManus B, Korpela R, O’Connor P, et al. Compared to casein, bovine lactoferrin reduces plasma leptin and corticosterone and affects hypothalamic gene expression without altering weight gain or fat mass in high fat diet fed C57/BL6J mice. Nutr Metab (Lond). 2015;12:53.
  35. Fang B, Zhang M, Tian M, et al. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET. Biochim Biophys Acta. 2014;1841(4):535-543.
  36. Соколов А.В., Власенко А.Ю., Костевич В.А., и др. Цитотоксические свойства комплексов лактоферрина с ненасыщенными жирными кислотами // Acta Naturae. – 2017. – T. 9. – № S. – С. 47. [Sokolov AV, Vlasenko AY, Kostevich VA, et al. Tsitotoksicheskie svoystva kompleksov laktoferrina s nenasyshchennymi zhirnymi kislotami. Acta Naturae. 2017;9(S):47. (In Russ.)]
  37. Соколов А.В., Власенко А.Ю., Костевич В.А., и др. Взаимодействие церулоплазмина с комплексом лактоферрина и олеиновой кислоты // Медицинский академический журнал. – 2016. – Т. 16. – № 4. – С. 233–234. [Sokolov AV, Vlasenko AY, Kostevich VA, et al. Vzaimodeystvie tseruloplazmina s kompleksom laktoferrina i oleinovoy kisloty. Med Acad J. 2016;16(4):233-234. (In Russ.)]
  38. Yen FT, Mann CJ, Guermani LM, et al. Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein. Biochemistry. 1994;33(5):1172-1180.
  39. Mann CJ, Khallou J, Chevreuil O, et al. Mechanism of Activation and Functional Significance of the Lipolysis-Stimulated Receptor. Evidence for a Role as Chylomicron Remnant Receptor. Biochemistry. 2002;34(33):10421-10431.
  40. Ahmad N, Girardet JM, Akbar S, et al. Lactoferrin and its hydrolysate bind directly to the oleate-activated form of the lipolysis stimulated lipoprotein receptor. FEBS J. 2012;279(23):4361-4373.
  41. Stenger C, Hanse M, Pratte D, et al. Up-regulation of hepatic lipolysis stimulated lipoprotein receptor by leptin: a potential lever for controlling lipid clearance during the postprandial phase. FASEB J. 2010;24(11):4218-4228.
  42. Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621-2637.
  43. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010;11(1):11-18.
  44. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415-1428.
  45. Moreno-Navarrete JM, Fernandez-Real JM. Antimicrobial-sensing proteins in obesity and type 2 diabetes: the buffering efficiency hypothesis. Diabetes Care. 2011;34 Suppl 2:S335-341.
  46. Benson TW, Weintraub NL, Kim HW, et al. A single high-fat meal provokes pathological erythrocyte remodeling and increases myeloperoxidase levels: implications for acute coronary syndrome. Lab Invest. 2018;98(10):1300-1310.
  47. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res. 2008;49(9):1894-1903.
  48. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761-1772.
  49. Walrand S, Guillet C, Boirie Y, Vasson MP. In vivo evidences that insulin regulates human polymorphonuclear neutrophil functions. J Leukoc Biol. 2004;76(6):1104-1110.
  50. Moreno-Navarrete JM, Ortega FJ, Bassols J, et al. Decreased circulating lactoferrin in insulin resistance and altered glucose tolerance as a possible marker of neutrophil dysfunction in type 2 diabetes. J Clin Endocrinol Metab. 2009;94(10):4036-4044.
  51. Moreno-Navarrete JM, Ortega FJ, Bassols J, et al. Association of circulating lactoferrin concentration and 2 nonsynonymous LTF gene polymorphisms with dyslipidemia in men depends on glucose-tolerance status. Clin Chem. 2008;54(2):301-309.
  52. Velliyagounder K, Kaplan JB, Furgang D, et al. One of Two Human Lactoferrin Variants Exhibits Increased Antibacterial and Transcriptional Activation Activities and Is Associated with Localized Juvenile Periodontitis. Infect Immun. 2003;71(11):6141-6147.
  53. Wu YM, Juo SH, Ho YP, et al. Association between lactoferrin gene polymorphisms and aggressive periodontitis among Taiwanese patients. J Periodontal Res. 2009;44(3):418-424.
  54. Fernandez-Real JM, Garcia-Fuentes E, Moreno-Navarrete JM, et al. Fat overload induces changes in circulating lactoferrin that are associated with postprandial lipemia and oxidative stress in severely obese subjects. Obesity (Silver Spring). 2010;18(3):482-488.
  55. Рудниченко Ю.А., Лукашевич В.С., Залуцкий И.В. Экспериментальное исследование влияния рекомбинантного лактоферрина человека на уровни андрогенов и основные показатели липидного и белкового обмена // Биомедицинская химия. – 2016. – Т. 62. – № 5. – С. 566–571. [Rudnichenko YA, Lukashevich VS, Zalutskiy IV. Experimental study of the influence of recombinant human lactoferrin on the levels of androgens and basic parameters of lipid and protein metabolism. Biomed Khim. 2016;62(5):566-571. (In Russ.)].
  56. Рудниченко Ю.А., Лукашевич В.С., Залуцкий И.В. Динамика изменения содержания половых гормонов в сыворотке крови крыс-самцов после завершения курсового введения рекомбинантного лактоферрина человека // Биофармацевтический журнал. – 2018. – Т. 10. – № 2. – C. 57–63. [Rudnichenko YA, Lukashevich VS, Zalutskiy IV. Changes in the sex hormones content in the blood serum of male rats after administration of the recombinant human lactoferrin. Biofarmatsevticheskii zhurnal. 2018;10(2):57-63. (In Russ.)]
  57. Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care. 2011;34(7):1669-1675.
  58. Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217(3):R25-45.
  59. Yagi M, Suzuki N, Takayama T, et al. Lactoferrin suppress the adipogenic differentiation of MC3T3-G2/PA6 cells. J Oral Sci. 2008;50(4):419-425.
  60. Moreno-Navarrete JM, Ortega FJ, Ricart W, Fernandez-Real JM. Lactoferrin increases (172Thr)AMPK phosphorylation and insulin-induced (p473Ser)AKT while impairing adipocyte differentiation. Int J Obes (Lond). 2009;33(9):991-1000.
  61. Nam MS, Cho MC, Bae HC, Yoon DY. Effects of lactoferrin on adipogenesis in 3T3-L1 cells and obesity mice. Biochem. Cell Biol. 2006;84(3):399.
  62. Moreno-Navarrete JM, Ortega F, Sabater M, et al. Proadipogenic effects of lactoferrin in human subcutaneous and visceral preadipocytes. J Nutr Biochem. 2011;22(12):1143-1149.
  63. Moreno-Navarrete JM, Serrano M, Sabater M, et al. Study of lactoferrin gene expression in human and mouse adipose tissue, human preadipocytes and mouse 3T3-L1 fibroblasts. Association with adipogenic and inflammatory markers. J Nutr Biochem. 2013;24(7):1266-1275.
  64. Moreno-Navarrete JM, Ortega F, Moreno M, et al. Lactoferrin gene knockdown leads to similar effects to iron chelation in human adipocytes. J Cell Mol Med. 2014;18(3):391-395.
  65. Mayeur S, Veilleux A, Pouliot Y, et al. Plasma Lactoferrin Levels Positively Correlate with Insulin Resistance despite an Inverse Association with Total Adiposity in Lean and Severely Obese Patients. PLoS One. 2016;11(11):e0166138.
  66. Vengen IT, Dale AC, Wiseth R, et al. Lactoferrin is a novel predictor of fatal ischemic heart disease in diabetes mellitus type 2: long-term follow-up of the HUNT 1 study. Atherosclerosis. 2010;212(2):614-620.
  67. Netea MG, Joosten LA, Lewis E, et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat Med. 2006;12(6):650-656.
  68. Ishii K. Long-term follow-up of chronic hepatitis C patients treated with oral lactoferrin for 12 months. Hepatol Res. 2003;25(3):226-233.
  69. Hayes TG, Falchook GF, Varadhachary GR, et al. Phase I trial of oral talactoferrin alfa in refractory solid tumors. Invest New Drugs. 2006;24(3):233-240.
  70. Ono T, Fujisaki C, Ishihara Y, et al. Potent lipolytic activity of lactoferrin in mature adipocytes. Biosci Biotechnol Biochem. 2013;77(3):566-571.
  71. Ikoma-Seki K, Nakamura K, Morishita S, et al. Role of LRP1 and ERK and cAMP Signaling Pathways in Lactoferrin-Induced Lipolysis in Mature Rat Adipocytes. PLoS One. 2015;10(10):e0141378.
  72. Morishita S, Tomita K, Ono T, et al. Lactoferrin attenuates fatty acid-induced lipotoxicity via Akt signaling in hepatocarcinoma cells. Biochem Cell Biol. 2015;93(6):566-573.
  73. Grey A, Zhu Q, Watson M, et al. Lactoferrin potently inhibits osteoblast apoptosis, via an LRP1-independent pathway. Mol Cell Endocrinol. 2006;251(1-2):96-102.
  74. Nakamura K, Kishida T, Ejima A, et al. Bovine lactoferrin promotes energy expenditure via the cAMP-PKA signaling pathway in human reprogrammed brown adipocytes. Biometals. 2018;31(3):415-424.
  75. Cao W, Medvedev AV, Daniel KW, Collins S. beta-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J Biol Chem. 2001;276(29):27077-27082.
  76. Kozak LP, Anunciado-Koza R. UCP1: its involvement and utility in obesity. Int J Obes (Lond). 2008;32 Suppl 7:S32-38.
  77. Baumrucker CR, Erondu NE. Insulin-like growth factor (IGF) system in the bovine mammary gland and milk. J Mammary Gland Biol Neoplasia. 2000;5(1):53-64.
  78. Mir R, Kumar RP, Singh N, et al. Specific interactions of C-terminal half (C-lobe) of lactoferrin protein with edible sugars: binding and structural studies with implications on diabetes. Int J Biol Macromol. 2010;47(1):50-59.
  79. Sharma S, Singh TP, Bhatia KL. Preparation and characterization of the N and C monoferric lobes of buffalo lactoferrin produced by proteolysis using proteinase K. J Dairy Res. 1999;66(1):81-90.
  80. Morishita S, Ono T, Fujisaki C, et al. Bovine lactoferrin reduces visceral fat and liver triglycerides in ICR mice. J Oleo Sci. 2013;62(2):97-103.
  81. Tamano S, Sekine K, Takase M, et al. Lack of chronic oral toxicity of chemopreventive bovine lactoferrin in F344/DuCrj rats. Asian Pac J Cancer Prev. 2008;9(2):313-316.
  82. Pilvi TK, Harala S, Korpela R, Mervaala EM. Effects of high-calcium diets with different whey proteins on weight loss and weight regain in high-fat-fed C57BL/6J mice. Br J Nutr. 2009;102(3):337-341.
  83. Shi J, Finckenberg P, Martonen E, et al. Metabolic effects of lactoferrin during energy restriction and weight regain in diet-induced obese mice. J Funct Foods. 2012;4(1):66-78.
  84. Singh A, Zapata RC, Pezeshki A, Chelikani PK. Dietary lactalbumin and lactoferrin interact with inulin to modulate energy balance in obese rats. Obesity (Silver Spring). 2017;25(6):1050-1060.
  85. Zapata RC, Singh A, Pezeshki A, et al. Whey Protein Components – Lactalbumin and Lactoferrin – Improve Energy Balance and Metabolism. Sci Rep. 2017;7(1):9917.
  86. Nozari S, Fathi Maroufi N, Nouri M, et al. Decreasing serum homocysteine and hypocholesterolemic effects of Bovine lactoferrin in male rat fed with high-cholesterol diet. J Cardiovasc Thorac Res. 2018;10(4):203-208.
  87. Min QQ, Qin LQ, Sun ZZ, et al. Effects of Metformin Combined with Lactoferrin on Lipid Accumulation and Metabolism in Mice Fed with High-Fat Diet. Nutrients. 2018;10(11).
  88. Kushibiki S, Shingu H, Komatsu T, et al. Influence of orally administered bovine lactoferrin on lipid metabolism in lipopolysaccharide-injected preruminant calves. Anim Sci J. 2009;80(3):258-264.
  89. Li YC, Hsieh CC. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model. PLoS One. 2014;9(5):e97341.
  90. Morishita S, Kawaguchi H, Ono T, et al. Enteric lactoferrin attenuates the development of high-fat and high-cholesterol diet-induced hypercholesterolemia and atherosclerosis in Microminipigs. Biosci Biotechnol Biochem. 2016;80(2):295-303.
  91. Sun J, Ren F, Xiong L, et al. Bovine lactoferrin suppresses high-fat diet induced obesity and modulates gut microbiota in C57BL/6J mice. J Funct Foods. 2016;22:189-200.
  92. Lee S, Son B, Jeon J, et al. Decreased Hepatic Lactotransferrin Induces Hepatic Steatosis in Chronic Non-Alcoholic Fatty Liver Disease Model. Cell Physiol Biochem. 2018;47(6):2233-2249.
  93. Hayashida K, Takeuchi T, Ozaki T, et al. Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats. Am J Physiol Regul Integr Comp Physiol. 2004;286(2):R359-365.
  94. Hayashida K, Takeuchi T, Shimizu H, et al. Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord. Am J Physiol Regul Integr Comp Physiol. 2003;285(2):R306-312.
  95. Lee NY, Cheng JT, Enomoto T, Nakamura I. The antihypertensive activity of angiotensin-converting enzyme inhibitory peptide containing in bovine lactoferrin. Chin J Physiol. 2006;49(2):67-73.
  96. Garcia-Tejedor A, Sanchez-Rivera L, Castello-Ruiz M, et al. Novel antihypertensive lactoferrin-derived peptides produced by Kluyveromyces marxianus: gastrointestinal stability profile and in vivo angiotensin I-converting enzyme (ACE) inhibition. J Agric Food Chem. 2014;62(7):1609-1616.
  97. Manzanares P, Salom JB, Garcia-Tejedor A, et al. Unraveling the mechanisms of action of lactoferrin-derived antihypertensive peptides: ACE inhibition and beyond. Food Funct. 2015;6(8):2440-2452.
  98. Ruiz-Gimenez P, Ibanez A, Salom JB, et al. Antihypertensive properties of lactoferricin B-derived peptides. J Agric Food Chem. 2010;58(11):6721-6727.
  99. Li H, Wang Y, Yang H, et al. Lactoferrin Induces the Synthesis of Vitamin B6 and Protects HUVEC Functions by Activating PDXP and the PI3K/AKT/ERK1/2 Pathway. Int J Mol Sci. 2019;20(3).
  100. Kimoto H. Case report of 4 patients on the improvement of serum lipids by the enteric-coated LF tablets. Progr Medicine. 2003;23:1519-1523.
  101. Ono T, Murakoshi M, Suzuki N, et al. Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br J Nutr. 2010;104(11):1688-1695.
  102. Mohamed WA, Schaalan MF. Antidiabetic efficacy of lactoferrin in type 2 diabetic pediatrics; controlling impact on PPAR-gamma, SIRT-1, and TLR4 downstream signaling pathway. Diabetol Metab Syndr. 2018;10:89.
  103. Zakharova ET, Sokolov AV, Pavlichenko NN, et al. Erythropoietin and Nrf2: key factors in the neuroprotection provided by apo-lactoferrin. Biometals. 2018;31(3):425-443.
  104. Li YM, Tan AX, Vlassara H. Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif. Nature Medicine. 1995;1(10):1057-1061.
  105. Takayama Y, Aoki R. Roles of lactoferrin on skin wound healing. Biochem Cell Biol. 2012;90(3):497-503.
  106. Lyons TE, Miller MS, Serena T, et al. Talactoferrin alfa, a recombinant human lactoferrin promotes healing of diabetic neuropathic ulcers: a phase 1/2 clinical study. Am J Surg. 2007;193(1):49-54.
  107. Norrby K. Human apo-lactoferrin enhances angiogenesis mediated by vascular endothelial growth factor A in vivo. J Vasc Res. 2004;41(4):293-304.
  108. Zakharova ET, Kostevich VA, Sokolov AV, Vasilyev VB. Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha. Biometals. 2012;25(6):1247-1259.
  109. Kostevich VA, Sokolov AV, Kozlov SO, et al. Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet. Biometals. 2016;29(4):691-704.
  110. Alnaeeli M, Noguchi CT. Erythropoietin and obesity-induced white adipose tissue inflammation: redefining the boundaries of the immunometabolism territory. Adipocyte. 2015;4(2):153-157.
  111. Kodo K, Sugimoto S, Nakajima H, et al. Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice. PLoS One. 2017;12(3):e0173661.
  112. Teng R, Gavrilova O, Suzuki N, et al. Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production. Nat Commun. 2011;2:520.
  113. Dey S, Li X, Teng R, et al. Erythropoietin regulates POMC expression via STAT3 and potentiates leptin response. J Mol Endocrinol. 2016;56(2):55-67.
  114. Xiong L, Ren F, Lv J, et al. Lactoferrin attenuates high-fat diet-induced hepatic steatosis and lipid metabolic dysfunctions by suppressing hepatic lipogenesis and down-regulating inflammation in C57BL/6J mice. Food Funct. 2018;9(8):4328-4339.
  115. Lankin VZ, Tikhaze AK, Kukharchuk VV, et al. Molecular and Cellular Biochemistry. 2003;249(1/2):129-140.
  116. Manzoni P, Stolfi I, Messner H, et al. Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: a randomized controlled trial. Pediatrics. 2012;129(1):116-123.
  117. Kozu T, Iinuma G, Ohashi Y, et al. Effect of orally administered bovine lactoferrin on the growth of adenomatous colorectal polyps in a randomized, placebo-controlled clinical trial. Cancer Prev Res (Phila). 2009;2(11):975-983.
  118. Ono T, Morishita S, Murakoshi M. Novel function of bovine lactoferrin in lipid metabolism: Visceral fat reduction by enteric-coated lactoferrin. PharmaNutrition. 2013;1(1):32-34.
  119. Scientific Opinion on bovine lactoferrin. EFSA J. 2012;10(5):2701.
  120. Борзенкова Н.В., Балабушевич Н.Г., Ларионова Н.И. Лактоферрин: физико-химические свойства, биологические функции, системы доставки, лекарственные препараты и биологически активные добавки (обзор) // Биофармацевтический журнал. – 2010. – Т. 2. – № 3. – С. 3–19. [Borzenkova NV, Balabushevich NG, Larionova NI. Lactoferrin: physical and chemical properties, biological functions, delivery systems, pharmaceutical and nutraceutical preparations (review). Biofarmatsevticheskii zhurnal. 2010;2(3):3-19. (In Russ.)]
  121. Соколов А.В., Пулина М.О., Кристиян А.В., и др. Исследование рекомбинантного лактоферрина человека, секретируемого в молоко трансгенных мышей // Доклады Академии наук. – 2006. – Т. 411. – № 2. – С. 267–270. [Sokolov AV, Pulina MO, Kristiyan AV, et al. A study of recombinant human lactoferrin secreted in milk of transgenic mice. Dokl Akad Nauk. 2006;411(2):336-338. (In Russ.)]

Supplementary files

Supplementary Files Action
1. Fig. 1. The effect of lactoferrin on binding lipoproteins including oxidized low density lipoproteins (LDLox) with receptors: LRP-1, LSR and scavenger-receptor View (86KB) Indexing metadata
2. Fig. 2. The effect of lactoferrin on lipids metabolism on brown fat (adapted [74]). AC — adenylate cyclase, cAMP — cyclic adenosine monophosphate, P — phosphorylation, PLIN — perilipin View (118KB) Indexing metadata
3. Fig. 3. Scheme summarized metabolism of lactoferrin and its effects in metabolic syndrome View (203KB) Indexing metadata


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