TY - JOUR
T1 - Vitamin D regulates macrophage cholesterol metabolism in diabetes
AU - Riek, Amy E.
AU - Oh, Jisu
AU - Bernal-Mizrachi, Carlos
N1 - Funding Information:
We thank Drs. Adriana Dusso for helpful discussions and review of the manuscript. This work was supported by American Diabetes Association (7-08-CR-08) and the David M. and Paula S. Kipnis Scholar in Medicine Award.
PY - 2010/7
Y1 - 2010/7
N2 - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). In type 2 diabetics, the prevalence of vitamin D deficiency is 20% higher than in non-diabetics, and low vitamin D levels nearly double the relative risk of developing CVD compared to diabetic patients with normal vitamin D levels. However, the mechanism(s) by which vitamin D deficiency leads to an increased susceptibility to atherosclerosis in these patients is unknown. We studied the effects of vitamin D replacement on macrophage cholesterol metabolism and foam cell formation in obese, hypertensive diabetics and non-diabetic controls. We found that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] suppressed foam cell formation by reducing acetylated low density lipoprotein (AcLDL) and oxidized low density lipoprotein (oxLDL) cholesterol uptake in diabetics only. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARγ and CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxLDL- and AcLDL-derived cholesterol uptake. The results of this research reveal novel insights into the mechanisms linking vitamin D signaling to foam cell formation in diabetics and suggest a potential new therapeutic target to reduce cardiovascular risk in this population.
AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). In type 2 diabetics, the prevalence of vitamin D deficiency is 20% higher than in non-diabetics, and low vitamin D levels nearly double the relative risk of developing CVD compared to diabetic patients with normal vitamin D levels. However, the mechanism(s) by which vitamin D deficiency leads to an increased susceptibility to atherosclerosis in these patients is unknown. We studied the effects of vitamin D replacement on macrophage cholesterol metabolism and foam cell formation in obese, hypertensive diabetics and non-diabetic controls. We found that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] suppressed foam cell formation by reducing acetylated low density lipoprotein (AcLDL) and oxidized low density lipoprotein (oxLDL) cholesterol uptake in diabetics only. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARγ and CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxLDL- and AcLDL-derived cholesterol uptake. The results of this research reveal novel insights into the mechanisms linking vitamin D signaling to foam cell formation in diabetics and suggest a potential new therapeutic target to reduce cardiovascular risk in this population.
KW - Cardiovascular disease
KW - Diabetes
KW - Macrophage cholesterol metabolism
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=77954758385&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2010.03.018
DO - 10.1016/j.jsbmb.2010.03.018
M3 - Article
C2 - 20338238
AN - SCOPUS:77954758385
SN - 0960-0760
VL - 121
SP - 430
EP - 433
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1-2
ER -