title: 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus.
abstract: BACKGROUND
  Cardiovascular disease is the leading cause of death among those with diabetes mellitus. Vitamin D deficiency is associated with an increased risk of cardiovascular disease in this population. To determine the mechanism by which vitamin D deficiency mediates accelerated cardiovascular disease in patients with diabetes mellitus, we investigated the effects of active vitamin D on macrophage cholesterol deposition.
  
  
  RESULTS
  We obtained macrophages from 76 obese, diabetic, hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D <80 nmol/L; group A) and 4 control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B; n=15); obese, nondiabetic, hypertensive patients with vitamin D deficiency (group C; n=25); and nonobese, nondiabetic, nonhypertensive patients with vitamin D deficiency (group D; n=10) or sufficiency (group E; n=10). Macrophages from the same patients in all groups were cultured in vitamin D-deficient or 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] -supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)(2)D(3) suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetic subjects only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam cell formation induced by modified LDL. 1,25(OH)(2)D(3) downregulation of c-Jun N-terminal kinase activation reduced peroxisome proliferated-activated receptor-gamma expression, suppressed CD36 expression, and prevented oxidized low-density lipoprotein-derived cholesterol uptake. In addition, 1,25(OH)(2)D(3) suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxidized and acetylated low-density lipoprotein-derived cholesterol uptake.
  
  
  CONCLUSIONS
  These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.
authors: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Jisu
authors: J
authors: Oh
authors: Sherry
authors: S
authors: Weng
authors: Shaili K
authors: SK
authors: Felton
authors: Sweety
authors: S
authors: Bhandare
authors: Amy
authors: A
authors: Riek
authors: Boyd
authors: B
authors: Butler
authors: Brandon M
authors: BM
authors: Proctor
authors: Marvin
authors: M
authors: Petty
authors: Zhouji
authors: Z
authors: Chen
authors: Kenneth B
authors: KB
authors: Schechtman
authors: Leon
authors: L
authors: Bernal-Mizrachi
authors: Carlos
authors: C
authors: Bernal-Mizrachi
mesh_terms: D000328:Adult; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009765:Obesity / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D014808:Vitamin D Deficiency / Q000276:immunology / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D018167:Receptors, Calcitriol; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D002784:Cholesterol; D048031:JNK Mitogen-Activated Protein Kinases