PMID- 23333932
OWN - NLM
STAT- MEDLINE
DCOM- 20130830
LR  - 20211021
IS  - 1879-1220 (Electronic)
IS  - 0960-0760 (Print)
IS  - 0960-0760 (Linking)
VI  - 136
DP  - 2013 Jul
TI  - 1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic 
      cholesterol metabolism in type 2 diabetic patients.
PG  - 309-12
LID - S0960-0760(13)00010-1 [pii]
LID - 10.1016/j.jsbmb.2012.12.019 [doi]
AB  - Reduced monocyte infiltration into the vessel wall and increased macrophage 
      cholesterol efflux are critical components in atherosclerotic plaque regression. 
      During inflammation, monocyte chemotactic protein 1 (MCP-1) signaling activation 
      and cholesterol deposition in macrophages induce endoplasmic reticulum (ER) 
      stress, which promotes an increased inflammatory response. Increased macrophage 
      ER stress shifts macrophages into an M2 macrophage phenotype with increased 
      cholesterol uptake and deposition. In type 2 diabetes, a population with elevated 
      baseline risk of cardiovascular disease (CVD), vitamin D deficiency doubles that 
      risk. We have found that 1,25-dihydroxy vitamin D [1,25(OH)2D] prevents foam cell 
      formation during macrophage differentiation by suppressing ER stress. However, it 
      is unknown whether suppression of ER stress by 1,25(OH)2D decreases monocyte 
      infiltration and reverses atherogenic cholesterol metabolism in previously 
      differentiated, vitamin D-deplete macrophages. We collected peripheral monocytes 
      from type 2 diabetic patients and differentiated them into macrophages under 
      vitamin D-deplete or 1,25(OH)2D-supplemented conditions. 1,25(OH)2D 
      supplementation suppressed macrophage migration in response to MCP-1 and mRNA 
      expression of chemokine (C-C motif) receptor 2 (CCR2), the MCP-1 receptor, 
      compared to vitamin D-deplete cells. Furthermore, inhibition of ER stress with 
      phenyl butyric acid resulted in similar effects even in vitamin D-deplete cells, 
      while induction of ER stress with Thapsigargin under 1,25(OH)2D-supplemented 
      conditions increased macrophage migration and CCR2 expression, suggesting that 
      the effects of vitamin D on migration are mediated through ER stress suppression. 
      To determine whether the detrimental pattern of macrophage cholesterol metabolism 
      in vitamin D depletion is reversible, we assessed cholesterol uptake in 
      macrophages differentiated under vitamin D-deplete conditions as described above, 
      then supplemented with 1,25(OH)2D or maintained in vitamin D-deplete conditions. 
      Cholesterol uptake was decreased in 1,25(OH)2D-supplemented compared to vitamin 
      D-deplete cells, suggesting slowed cholesterol deposition with active vitamin D. 
      1,25(OH)2D supplementation also suppressed cholesteryl ester formation and 
      enhanced cholesterol efflux in M2 macrophages compared to vitamin D-deplete 
      cells, suggesting facilitation of cholesterol egress in the presence of 
      1,25(OH)2D. We thus provide further evidence that active vitamin D is an ER 
      stress reliever that may have a role in atherosclerotic plaque regression. This 
      article is part of a Special Issue entitled 'Vitamin D Workshop'.
CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
FAU - Riek, Amy E
AU  - Riek AE
AD  - Division of Endocrinology, Metabolism, and Lipid Research, Washington University, 
      660 South Euclid Avenue, Campus Box 8127, St. Louis, MO 63110, USA. 
      ariek@dom.wustl.edu
FAU - Oh, Jisu
AU  - Oh J
FAU - Bernal-Mizrachi, Carlos
AU  - Bernal-Mizrachi C
LA  - eng
GR  - P30DK079333/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341/DK/NIDDK NIH HHS/United States
GR  - R01 HL094818/HL/NHLBI NIH HHS/United States
GR  - UL1 TR000448/TR/NCATS NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - P30 DK079333/DK/NIDDK NIH HHS/United States
GR  - KL2 TR000450/TR/NCATS NIH HHS/United States
GR  - R01HL094818/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20130117
PL  - England
TA  - J Steroid Biochem Mol Biol
JT  - The Journal of steroid biochemistry and molecular biology
JID - 9015483
RN  - 0 (Anticholesteremic Agents)
RN  - 1406-16-2 (Vitamin D)
RN  - 66772-14-3 (1,25-dihydroxyvitamin D)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Anticholesteremic Agents/*pharmacology
MH  - Atherosclerosis/prevention & control
MH  - Cell Migration Inhibition/*drug effects
MH  - Cholesterol/adverse effects/*metabolism
MH  - Diabetes Mellitus, Type 2/*drug therapy/*pathology
MH  - Endoplasmic Reticulum Stress/drug effects
MH  - Humans
MH  - Macrophages/*drug effects/physiology
MH  - Plaque, Atherosclerotic/drug therapy
MH  - Vitamin D/*analogs & derivatives/physiology
PMC - PMC3687029
MID - NIHMS437158
EDAT- 2013/01/22 06:00
MHDA- 2013/08/31 06:00
PMCR- 2014/07/01
CRDT- 2013/01/22 06:00
PHST- 2012/07/07 00:00 [received]
PHST- 2012/12/27 00:00 [revised]
PHST- 2012/12/28 00:00 [accepted]
PHST- 2013/01/22 06:00 [entrez]
PHST- 2013/01/22 06:00 [pubmed]
PHST- 2013/08/31 06:00 [medline]
PHST- 2014/07/01 00:00 [pmc-release]
AID - S0960-0760(13)00010-1 [pii]
AID - 10.1016/j.jsbmb.2012.12.019 [doi]
PST - ppublish
SO  - J Steroid Biochem Mol Biol. 2013 Jul;136:309-12. doi: 
      10.1016/j.jsbmb.2012.12.019. Epub 2013 Jan 17.