Ukr.Biochem.J. 2020; Volume 92, Issue 4, Jul-Aug, pp. 5-13


Vitamin D(3) regulates hepatic VEGF-A and apelin expression in experimental type 1 diabetes

D. O. Labudzynskyi1*, I. O. Shymanskyi1, O. O. Lisakovska1,
A. O. Mazanova1, L. V. Natrus2, M. M. Veliky1

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
2Bogomolets National Medical University, Kyiv, Ukraine;

Received: 09 July 2019; Accepted: 15 May 2020

The deficiency of vitamin D is associated with the risk of various chronic diseases, including diabetes mellitus and its complications. Given the strong genomic action of vitamin D hormone-active form, its deficiency can lead to dysfunction of cytokine signaling pathways, including those dependent on vascular endothelial growth factors (VEGFs) and apelin. The present study was carried out to define the link between VEGF-A and apelin expression in liver, hepatocytes viability and vitamin D status at experimental type 1 diabetes in mice. We established that chronic hyperglycemia at streptozotocin-induced diabetes was accompanied by a 2.2-fold decrease in 25OHD content in the serum and increased hepatocytes apoptosis and necrosis. Vitamin D deficiency correlated with increased apelin and VEGF-A (8- and 1.6-fold respectively) expression. Almost complete restoration of circulatory 25OHD content in serum was achieved at vitamin D3 treatment (800 IU/kg, per os, for 2 months) followed by reduced apelin and VEGF-A expression in liver and the decline of hepatocytes apoptosis. We conclude that vitamin D3 can be involved in cell survival, angiogenesis and fibrogenesis by modulating  VEGF-A and apelin dependent regulatory systems in diabetic liver.

Keywords: , , , , , ,


  1. Pietropaolo M, Barinas-Mitchell E, Kuller LH. The heterogeneity of diabetes: Unraveling a dispute: Is systemic inflammation related to islet autoimmunity? Diabetes. 2007;56(5):1189-1197. PubMed, CrossRef
  2. Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018;14(2):99-114. PubMed, CrossRef
  3. Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag. 2008;4(3):575-596. PubMed, PubMedCentral, CrossRef
  4. Yang L, Kwon J, Popov Y, Gajdos GB, Ordog T, Brekken RA, Mukhopadhyay D, Schuppan D, Bi Y, Simonetto D, Shah VH. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology. 2014;146(5):1339-1350.e1. PubMed, PubMed, CrossRef
  5. Principe A, Melgar-Lesmes P, Fernández-Varo G, del Arbol LR, Ros J, Morales-Ruiz M, Bernardi M, Arroyo V, Jiménez W. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology. 2008;48(4):1193-1201.  PubMed, CrossRef
  6. Huang Z, Luo X, Liu M, Chen L. Function and regulation of apelin/APJ system in digestive physiology and pathology. J Cell Physiol. 2019;234(6):7796-7810. PubMed, CrossRef
  7. Masri B, van den Berghe L, Sorli C, Knibiehler B, Audigier Y. Apelin signalisation and vascular physiopathology. J Soc Biol. 2009;203(2):171-179. PubMed, CrossRef
  8. Zendehdel A, Arefi M. Molecular evidence of role of vitamin D deficiency in various extraskeletal diseases. J Cell Biochem. 2019;120(6):8829-8840. PubMed, CrossRef
  9. Iruzubieta P, Terán Á, Crespo J, Fábrega E. Vitamin D deficiency in chronic liver disease. World J Hepatol. 2014;6(12):901-915. PubMed, PubMed, CrossRef
  10. Komisarenko YI, Bobryk MI. Vitamin D deficiency and immune disorders in combined endocrine pathology. Front Endocrinol (Lausanne). 2018;9:600. PubMed, PubMed, CrossRef
  11. Like AA, Rossini AA. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science. 1976; 193(4251): 415-7. PubMed, CrossRef
  12. Marcotorchino J, Romier B, Gouranton E, Riollet C, Gleize B, Malezet-Desmoulins C, Landrier JF. Lycopene attenuates LPS-induced TNF-alpha secretion in macrophages and inflammatory markers in adipocytes exposed to macrophage-conditioned media. Mol Nutr Food Res. 2012;56(5):725-32. PubMed, CrossRef
  13. Gu J, Tong XS, Chen GH, Wang D, Chen Y, Yuan Y, Liu XZ, Bian JC, Liu ZP. Effects of 1α,25-(OH)2D3 on the formation and activity of osteoclasts in RAW264.7 cells. J Steroid Biochem Mol Biol. 2015;152:25-33.  PubMed, CrossRef
  14. Walter D, Schmich K, Vogel S, Pick R, Kaufmann T, Hochmuth FC, Haber A, Neubert K, McNelly S, von Weizsäcker F, Merfort I, Maurer U, Strasser A, Borner C. Switch from type II to I Fas/CD95 death signaling upon in vitro culturing of primary hepatocytes. Hepatology. 2008;48(6):1942–1953. PubMed, PubMed, CrossRef
  15. Ning B, Bai M, Shen W. Reduced glutathione protects human hepatocytes from palmitate-mediated injury by suppressing endoplasmic reticulum stress response. Hepatogastroenterology. 2011;58(110-111):1670-1679. PubMed, CrossRef
  16. Mazanova A, Shymanskyi I, Lisakovska O, Hajiyeva L, Komisarenko Y, Veliky M. Effects of cholecalciferol on key components of vitamin D-endo/para/autocrine system in experimental type 1 diabetes. Int J Endocrinol. 2018;2018:2494016. PubMed, PubMed, CrossRef
  17. Kolluru GK, Bir SC, Kevil CG. Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int J Vasc Med. 2012;2012:918267. PubMed, PubMed, CrossRef
  18. Guzyk MM, Dyakun KO, Yanytska LV, Pryvrotska IB, Krynytska IYa, Pishel’ IM, Kuchmerovska TM. Inhibitors of Poly(ADP-Ribose)Polymerase-1 as Agents Providing Correction of Brain Dysfunctions Induced by Experimental Diabetes. Neurophysiology. 2017;49(3):183-193.  CrossRef
  19. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage. Sultan Qaboos Univ Med J. 2016;16(2):e132–141. PubMed, PubMed, CrossRef
  20. Zhou Q, Cao J, Chen L. Apelin/APJ system: a novel therapeutic target for oxidative stress-related inflammatory diseases (Review). Int J Mol Med. 2016;37(5):1159-1169. PubMed, CrossRef
  21. Lv SY, Cui B, Chen WD, Wang YD. Apelin/APJ system: A key therapeutic target for liver disease. Oncotarget. 2017;8(67):112145-112151.  PubMed, PubMed, CrossRef
  22. Hu H, He L, Li L, Chen L. Apelin/APJ system as a therapeutic target in diabetes and its complications. Mol Genet Metab. 2016;119(1-2):20-27. PubMed, CrossRef
  23. Huang C, Dai C, Gong K, Zuo H, Chu H. Apelin-13 protects neurovascular unit against ischemic injuries through the effects of vascular endothelial growth factor. Neuropeptides. 2016; 60: 67-74. PubMed, CrossRef
  24. Chaves-Almagro C, Castan-Laurell I, Dray C, Knauf C, Valet P, Masri B. Apelin receptors: from signaling to antidiabetic strategy. Eur J Pharmacol. 2015;763(Pt B):149-159. PubMed, CrossRef
  25. Chen H, Liu C, Cheng C, Zheng L, Huang K. Effects of apelin peptides on diabetic complications. Curr Protein Pept Sci. 2018;19(2):179-189.
    PubMed, CrossRef
  26. Huang S, Chen L, Lu L, Li L. The apelin-APJ axis: a novel potential therapeutic target for organ fibrosis. Clin Chim Acta. 2016; 456: 81-88. PubMed, CrossRef
  27. Lv X, Kong J, Chen WD, Wang YD. The Role of the apelin/APJ system in the regulation of liver disease. Front Pharmacol. 2017;8:221. PubMed, PubMed, CrossRef
  28. Wang C, Wen J, Zhou Y, Li L, Cui X, Wang J, Pan L, Ye Z, Liu P, Wu L. Apelin induces vascular smooth muscle cells migration via a PI3K/Akt/FoxO3a/MMP-2 pathway. Int J Biochem Cell Biol. 2015; 69: 173-82. PubMed, PubMed, CrossRef
  29. Shao Y, Lv C, Yuan Q, Wang Q. Levels of serum 25(OH)VD3, HIF-1α, VEGF, vWf, and IGF-1 and their correlation in type 2 diabetes patients with different urine albumin creatinine ratio. J Diabetes Res. 2016; 2016: 1925424. PubMed, PubMed, CrossRef
  30. Koszowska AU, Nowak J, Dittfeld A, Brończyk-Puzoń A, Kulpok A, Zubelewicz-Szkodzińska B. Obesity, adipose tissue function and the role of vitamin D. Cent Eur J Immunol. 2014;39(2):260-264. PubMed, PubMed, CrossRef
  31. Sarkar S, Chopra S, Rohit MK, Banerjee D, Chakraborti A. Vitamin D regulates the production of vascular endothelial growth factor: a triggering cause in the pathogenesis of rheumatic heart disease? Med Hypotheses. 2016; 95: 62-66.  PubMed, CrossRef
  32. Jamali N, Sorenson CM, Sheibani N. Vitamin D and regulation of vascular cell function. Am J Physiol Heart Circ Physiol. 2018; 314(4):H753-765. PubMed, PubMed, CrossRef
  33. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016; 96(1): 365-408. PubMed, PubMed, CrossRef
  34. Cardus A, Panizo S, Encinas M, Dolcet X, Gallego C, Aldea M, Fernandez E, Valdivielso JM. 1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter. Atherosclerosis. 2009; 204(1): 85-89. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.