Oh Jisu, Riek Amy E, Darwech Isra, Funai Katsuhiko, Shao JianSu, Chin Kathleen, Sierra Oscar L, Carmeliet Geert, Ostlund Richard E, Bernal-Mizrachi Carlos
Cell Rep. 2015 Mar 24;10(11):1872-86. doi: 10.1016/j.celrep.2015.02.043.
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 into the 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.
由于慢性全身性炎症会导致心脏代谢疾病，人们已投入大量精力来了解其易感性。我们证明，在小鼠中敲除巨噬细胞维生素D受体（VDR）（KODMAC）足以通过促进肝脏中M2巨噬细胞的积累以及增加细胞因子分泌和肝脏葡萄糖生成来诱导胰岛素抵抗。此外，VDR缺失会通过使富含脂质的M2单核细胞粘附、迁移并将胆固醇携带到动脉粥样硬化斑块中，以及增加巨噬细胞胆固醇摄取和酯化来加重动脉粥样硬化。VDR与肌浆网钙ATP酶2b（SERCA2b）相互作用的缺失导致SERCA功能障碍、内质网应激-钙/钙调蛋白依赖性蛋白激酶II-JNK通路（ER stress-CaMKII-JNKp）-过氧化物酶体增殖物激活受体γ（PPARγ）信号激活以及清道夫受体CD36和SR-A1的诱导，从而导致泡沫细胞形成增加。将表达VDR的细胞进行骨髓移植到KODMAC小鼠体内可改善胰岛素敏感性、抑制动脉粥样硬化并减少泡沫细胞形成。因此，维生素D在巨噬细胞中的免疫调节作用对于饮食诱导的小鼠胰岛素抵抗和动脉粥样硬化至关重要。
