TY - JOUR
T1 - Deletion of macrophage vitamin D receptor promotes insulin resistance and monocyte cholesterol transport to accelerate atherosclerosis in mice
AU - Oh, Jisu
AU - Riek, Amy E.
AU - Darwech, Isra
AU - Funai, Katsuhiko
AU - Shao, Jian Su
AU - Chin, Kathleen
AU - Sierra, Oscar L.
AU - Carmeliet, Geert
AU - Ostlund, Richard E.
AU - Bernal-Mizrachi, Carlos
N1 - Funding Information:
This work was supported by grants from the NIH (R01HL094818-0), Children’s Discovery Institute (CH-II-2012-209), and the American Diabetes Association (1-12-CT-08). A.E.R. was supported by grant K12HD001459 and the Washington University ICTS and by grants UL1 TR000448 and KL2 TR000450 from NCATS. K.F. was supported by grants T32 DK007120 and P60 DK20579. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of NIH. We would like to thank Dr. Clay F. Semenkovich for his thoughtful guidance, Dr. Mark Sands for his insightful comments and for sharing his expertise in BM transplant and Dr. Nicholas Davidson for his assistance in hepatocyte isolation.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/3/24
Y1 - 2015/3/24
N2 - Intense effort has been devoted to understanding predisposition to chronic systemic inflammation because it contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver as well as increasing cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol intothe atherosclerotic plaque and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp-PPARγ signaling, and induction of the scavenger receptors CD36 and SR-A1. Bone marrow transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet-induced insulin resistance and atherosclerosis in mice.
AB - Intense effort has been devoted to understanding predisposition to chronic systemic inflammation because it contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver as well as increasing cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol intothe atherosclerotic plaque and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp-PPARγ signaling, and induction of the scavenger receptors CD36 and SR-A1. Bone marrow transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet-induced insulin resistance and atherosclerosis in mice.
UR - http://www.scopus.com/inward/record.url?scp=84925681813&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.02.043
DO - 10.1016/j.celrep.2015.02.043
M3 - Article
C2 - 25801026
AN - SCOPUS:84925681813
SN - 2211-1247
VL - 10
SP - 1872
EP - 1886
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -