Deletion of Macrophage Vitamin D Receptor Promotes Insulin Resistance and Monocyte Cholesterol Transport to Accelerate Atherosclerosis in Mice

Abstract

Summary Intense effort has been devoted to understanding predisposition to chronic systemic inflammation as this 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 increase 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. BM 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. Graphical Abstract

The Role of Vitamin D in the Immune System as a Pro-survival Molecule

“…[110][111][112] Conversely, in monocytes/macrophages, the expression of 1α-hydroxylases is regulated by IFN-γ and the CD14/TLR4 interaction, in a synergistic way, due to the molecular action of C/EPB-β, Clinical Therapeutics following the activation of signaling pathways involving p38MAPK, JAK/STAT, and NF-κB. 113 At least as observed in animal models, vitamin D (mainly through its VDR) exerts a fundamental role on macrophage activity and polarization, particularly in their ability to respond to injury causing an inflammatory reaction.…”

Vitamin D Insufficiency Predicts Elevated Levels of Complement 3 Independent of Insulin Resistance and BMI

“…Vitamin D receptors (VDR) are found almost in all cells, including adipocytes and pancreatic b-cells and they have a great affinity for the active form of vitamin D (30). VDR removal found to be associated with IR development as more alternatively activated macrophages (M2) accumulate, more cytokines are produced, and hepatic glucose production is highly promoted (31). Yet, the imbalance between pro and anti-inflammatory biomarkers is one of the suggested mechanisms that explains the association between 25(OH)D and IR (29).…”

Vitamin D: Way More Important in Critical Care Than We May Have Recognized

“…When bone marrow transplants restored VDRs to macrophages and monocytes, the laudatory benefits of vitamin D appeared: atherosclerosis suppression, insulin sensitivity, and lack of macrophage accumulation. 56 …”