Altered signaling through the vitamin D receptor on certain immune cells may play a role in causing the chronic inflammation that leads to cardiometabolic disease, the combination of type 2 diabetes and heart disease that is the most common cause of illness and death in Western populations. The research appears March 19 in the journal Cell Reports.
"Because low vitamin D levels are associated with diabetes and heart disease, we looked at the connections between vitamin D, immune function, and these disease states," says senior author Carlos Bernal-Mizrachi, of the Washington University School of Medicine, in St. Louis.
The investigators found that when they engineered mice to lack expression of the vitamin D receptor in immune cells called monocytes and macrophages, the animals accumulated atherosclerotic plaques in their blood vessels and developed insulin resistance, meaning that their liver cells had a diminished ability to respond to insulin and regulate blood glucose levels.
"Inactivation of the macrophage vitamin D receptor promotes inflammation of the liver and of the artery walls. It also increases the ability of blood monocytes to adhere and migrate into the vessel wall, where they deposit cholesterol and secrete inflammatory mediators to cause diabetes and heart disease," explains Dr. Bernal-Mizrachi. "This implies that vitamin D will reduce these properties in immune cells to decrease inflammation and reduce the risk of cardiometabolic disease."
The research team found that bone marrow transplantation of cells that expressed the vitamin D receptor into mice lacking the vitamin D receptor in monocyte and macrophages improved the animals' insulin sensitivity, suppressed atherosclerosis, and decreased the formation of fat-laden macrophages that accumulate along blood vessel walls.
These results suggest that individuals may experience increased inflammation and serious health consequences when their immune cells are exposed to vitamin D deficiency or cannot process vitamin D. Indeed, findings from previous studies suggest that individuals with vitamin D deficiency have an increased risk of developing diabetes and that adequate dietary vitamin D in patients with diabetes limits the formation of fat-laden macrophages and decreases atherosclerosis.
"Our findings provide further mechanistic foundation for multiple interventional trials, including our own, to evaluate the effects of vitamin D on cardiometabolic disease," says Bernal-Mizrachi. "In addition, the identification of monocyte cholesterol transport as a mechanism for atherosclerosis in our animal model opens up a new area of research that could identify novel therapies for heart disease."
This work was supported by the National Institutes of Health, the Children's Discovery Institute and the American Diabetes Association.
Cell Reports, Oh et al.:"Deletion of Macrophage Vitamin D Receptor Promotes Insulin Resistance and Monocyte Cholesterol Transport to Accelerate Atherosclerosis in Mice"
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