Nutrition Research and Practice

The Korean Nutrition Society (한국영양학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of an in vitro vitamin D treatment on the inflammatory responses in visceral adipose tissue from Ldlr-/- mice

  • Deok Hoon Kwon (Department of Food and Nutrition, College of Human Ecology, Seoul National University) ;
  • Jungwon Hwang (Department of Food and Nutrition, College of Human Ecology, Seoul National University) ;
  • Hyeyoung You (Department of Food and Nutrition, College of Human Ecology, Seoul National University) ;
  • Na Young Kim (Department of Food and Nutrition, College of Human Ecology, Seoul National University) ;
  • Ga Young Lee (Department of Food and Nutrition, College of Human Ecology, Seoul National University) ;
  • Sung Nim Han (Department of Food and Nutrition, College of Human Ecology, Seoul National University)
  • Received : 2023.07.31
  • Accepted : 2023.11.16
  • Published : 2024.02.01
Download PDF
⟨ Previous Next ⟩

Abstract

BACKGROUND/OBJECTIVES: Atherosclerosis is associated with increased inflammation in the visceral adipose tissue (VAT). Vitamin D has been reported to modulate the inflammatory responses of stromal vascular cells (SVCs) and adipocytes in adipose tissue, but the role of vitamin D in atherosclerosis biology is unclear. This study examined the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) treatment on the inflammatory responses of SVCs and adipocytes from atherosclerotic mice. MATERIALS/METHODS: C57BL/6J (B6) mice were divided randomly into 2 groups and fed a 10% kcal fat control diet (control group, CON) or 41% kcal fat, 0.21% cholesterol (high fat + cholesterol, HFC) diet (obese group, OB), and B6.129S7-Ldlrtm1Her/J (Ldlr-/-) mice were fed a HFC diet (obese with atherosclerosis group, OBA) for 16 weeks. SVCs and adipocytes isolated from VAT were pre-incubated with 1,25(OH)2D3 for 24 h and stimulated with lipopolysaccarides for the next 24 h. Proinflammatory cytokine production by adipocytes and SVCs, the immune cell population in SVCs, and the expression of the genes involved in the inflammatory signaling pathway in SVCs were determined. RESULTS: The numbers of total macrophages and SVCs per mouse were higher in OB and OBA groups than the CON group. The in vitro 1,25(OH)2D3 treatment significantly reduced macrophages/SVCs (%) in the OBA group. Consistent with this change, the production of interleukin-6 and monocyte chemoattractant protein 1 (MCP-1) by SVCs from the OBA group was decreased by 1,25(OH)2D3 treatment. The 1,25(OH)2D3 treatment significantly reduced the toll-like receptor 4 and dual-specificity protein phosphatase 1 (also known as mitogen-activated protein kinase phosphatase 1) mRNA levels in SVCs and MCP-1 production by adipocytes from all 3 groups. CONCLUSIONS: These findings suggest that vitamin D can attribute to the inhibition of the inflammatory response in VAT from atherosclerotic mice by reducing proinflammatory cytokine production.

Keywords

Acknowledgement

The authors are thankful to Dae-Yong Kim, who kindly helped the authors with the technique of isolation and excision of the murine aorta.

References

  1. Libby P. The changing landscape of atherosclerosis. Nature 2021;592:524-33.
  2. Ross R, Neeland IJ, Yamashita S, Shai I, Seidell J, Magni P, Santos RD, Arsenault B, Cuevas A, Hu FB, et al. Waist circumference as a vital sign in clinical practice: a Consensus Statement from the IAS and ICCR Working Group on Visceral Obesity. Nat Rev Endocrinol 2020;16:177-89.
  3. Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 2014;1842:446-62.
  4. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-808.
  5. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-30.
  6. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847-50.
  7. Fain JN, Bahouth SW, Madan AK. TNFα release by the nonfat cells of human adipose tissue. Int J Obes 2004;28:616-22.
  8. Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol 2014;63:250-9.
  9. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010;11:11-8.
  10. Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20-34.
  11. Fantuzzi G, Mazzone T. Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol 2007;27:996-1003.
  12. Neeland IJ, Ross R, Despres JP, Matsuzawa Y, Yamashita S, Shai I, Seidell J, Magni P, Santos RD, Arsenault B, et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol 2019;7:715-25.
  13. Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis 2014;233:104-12.
  14. Ohman MK, Wright AP, Wickenheiser KJ, Luo W, Eitzman DT. Visceral adipose tissue and atherosclerosis. Curr Vasc Pharmacol 2009;7:169-79.
  15. Gustafson B. Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb 2010;17:332-41.
  16. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2010;10:826-37.
  17. Cole JE, Georgiou E, Monaco C. The expression and functions of toll-like receptors in atherosclerosis. Mediators Inflamm 2010;2010:393946.
  18. Sepehri Z, Kiani Z, Nasiri AA, Kohan F. Toll-like receptor 2 and type 2 diabetes. Cell Mol Biol Lett 2016;21:2.
  19. Wang Z, Ni X, Zhang L, Sun L, Zhu X, Zhou Q, Yang Z, Yuan H. Toll-like receptor 4 and inflammatory micro-environment of pancreatic islets in type-2 diabetes mellitus: a therapeutic perspective. Diabetes Metab Syndr Obes 2020;13:4261-72.
  20. Roshan MH, Tambo A, Pace NP. The role of TLR2, TLR4, and TLR9 in the pathogenesis of atherosclerosis. Int J Inflamm 2016;2016:1532832.
  21. Park CY, Han SN. The role of vitamin D in adipose tissue biology: adipocyte differentiation, energy metabolism, and inflammation. J Lipid Atheroscler 2021;10:130-44.
  22. Ding C, Gao D, Wilding J, Trayhurn P, Bing C. Vitamin D signalling in adipose tissue. Br J Nutr 2012;108:1915-23.
  23. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, Zugel U, Steinmeyer A, Pollak A, Roth E, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 2006;36:361-70.
  24. Dickie LJ, Church LD, Coulthard LR, Mathews RJ, Emery P, McDermott MF. Vitamin D3 down-regulates intracellular Toll-like receptor 9 expression and Toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatology (Oxford) 2010;49:1466-71.
  25. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, Goleva E. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 2012;188:2127-35.
  26. Park CY, Kim TY, Yoo JS, Seo Y, Pae M, Han SN. Effects of 1,25-dihydroxyvitamin D3 on the inflammatory responses of stromal vascular cells and adipocytes from lean and obese mice. Nutrients 2020;12:12.
  27. Lorente-Cebrian S, Eriksson A, Dunlop T, Mejhert N, Dahlman I, Astrom G, Sjolin E, Wahlen K, Carlberg C, Laurencikiene J, et al. Differential effects of 1α,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human white adipocytes. Eur J Nutr 2012;51:335-42.
  28. Marcotorchino J, Gouranton E, Romier B, Tourniaire F, Astier J, Malezet C, Amiot MJ, Landrier JF. Vitamin D reduces the inflammatory response and restores glucose uptake in adipocytes. Mol Nutr Food Res 2012;56:1771-82.
  29. Gao D, Trayhurn P, Bing C. 1,25-Dihydroxyvitamin D3 inhibits the cytokine-induced secretion of MCP-1 and reduces monocyte recruitment by human preadipocytes. Int J Obes 2013;37:357-65.
  30. Ding C, Wilding JP, Bing C. 1,25-Dihydroxyvitamin D3 protects against macrophage-induced activation of NFκB and MAPK signalling and chemokine release in human adipocytes. PLoS One 2013;8:e61707.
  31. Karkeni E, Marcotorchino J, Tourniaire F, Astier J, Peiretti F, Darmon P, Landrier JF. Vitamin D limits chemokine expression in adipocytes and macrophage migration in vitro and in male mice. Endocrinology 2015;156:1782-93.
  32. Sun X, Zemel MB. Calcitriol and calcium regulate cytokine production and adipocyte-macrophage cross-talk. J Nutr Biochem 2008;19:392-9.
  33. Sun X, Zemel MB. Calcium and 1,25-dihydroxyvitamin D3 regulation of adipokine expression. Obesity (Silver Spring) 2007;15:340-8.
  34. Surdu AM, Pinzariu O, Ciobanu DM, Negru AG, Cainap SS, Lazea C, Iacob D, Saraci G, Tirinescu D, Borda IM, et al. Vitamin D and its role in the lipid metabolism and the development of atherosclerosis. Biomedicines 2021;9:172.
  35. Riek AE, Oh J, Bernal-Mizrachi C. 1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients. J Steroid Biochem Mol Biol 2013;136:309-12.
  36. Riek AE, Oh J, Sprague JE, Timpson A, de las Fuentes L, Bernal-Mizrachi L, Schechtman KB, BernalMizrachi C. Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem 2012;287:38482-94.
  37. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772-83.
  38. Coenen KR, Gruen ML, Chait A, Hasty AH. Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue. Diabetes 2007;56:564-73.
  39. Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab 2005;90:2282-9.
  40. Chang E. Effects of vitamin D supplementation on adipose tissue inflammation and NF-κB/AMPK activation in obese mice fed a high-fat diet. Int J Mol Sci 2022;23:23.
  41. Jimenez-Martinez M, Stamatakis K, Fresno M. The dual-specificity phosphatase 10 (DUSP10): its role in cancer, inflammation, and immunity. Int J Mol Sci 2019;20:1626.
  42. Bijnen M, van de Gaar J, Vroomen M, Gijbels MJ, de Winther M, Schalkwijk CG, Wouters K. Adipose tissue macrophages do not affect atherosclerosis development in mice. Atherosclerosis 2019;281:31-7.
  43. Luo LJ, Liu F, Wang XY, Dai TY, Dai YL, Dong C, Ge BX. An essential function for MKP5 in the formation of oxidized low density lipid-induced foam cells. Cell Signal 2012;24:1889-98.
  44. Zhang X, Zhao Z, Baldini M, Zhang C, Tao B, Zhang L, Bennett AM, Yu J. Lack of mitogen-activated kinase phosphatase-5 in macrophages protects Ldlr-null mice against atherogenesis. JVS Vasc Sci 2022;3:423.
  45. Cohen-Lahav M, Shany S, Tobvin D, Chaimovitz C, Douvdevani A. Vitamin D decreases NFκB activity by increasing IκBα levels. Nephrol Dial Transplant 2006;21:889-97.
  46. Watanabe Y, Nagai Y, Takatsu K. Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance. Nutrients 2013;5:3757-78. 
  47. Uematsu S, Akira S. Toll-like receptors and innate immunity. J Mol Med (Berl) 2006;84:712-25.
  48. Ding Y, Subramanian S, Montes VN, Goodspeed L, Wang S, Han C, Teresa AS 3rd, Kim J, O'Brien KD, Chait A. Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2012;32:1596-604.
  49. Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 2007;26:3203-13.
  50. Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARα: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal 2010;8:e002.
  51. Wu JJ, Roth RJ, Anderson EJ, Hong EG, Lee MK, Choi CS, Neufer PD, Shulman GI, Kim JK, Bennett AM. Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab 2006;4:61-73.
  52. Khadir A, Tiss A, Abubaker J, Abu-Farha M, Al-Khairi I, Cherian P, John J, Kavalakatt S, Warsame S, Al-Madhoun A, et al. MAP kinase phosphatase DUSP1 is overexpressed in obese humans and modulated by physical exercise. Am J Physiol Endocrinol Metab 2015;308:E71-83.