Abstract 307: Influence of Dendritic Cells on Cholesterol Absorption and Excretion: Implication in Atherogenesis

Atherosclerosis represents the chronic pathophysiological process implicated in the majority of cardiovascular (CV) diseases and constitutes one of the leading causes of death in the world. The development of atherosclerotic lesions is characterized by an accumulation of extracellular and intracellular lipids in the arterial wall. These phenomena are associated with a strong local immuno-inflammatory response characterized by the recruitment of various populations of leucocytes including monocytes, macrophages and dendritic cells (DCs). DCs are central to the regulation of immunity and the polarization of the immune response. We recently demonstrated that the longevity/depletion of DCs directly impacts plasma cholesterol levels, which is the main risk factor for atherosclerosis. To gain insight into the cellular and molecular mechanisms underlying the inverse relationship between DC numbers and cholesterolemia, we have evaluated the impact of DCs on cholesterol homeostasis, using CD11c-hBcl2/apoE KO mice, in which specific DC-expression of the anti-apoptotic transgene hBcl2 increase their longevity and numbers. Firstly, we quantified DC populations in the liver and in the intestine, which are the main organs involved in cholesterol metabolism. Secondly, we measured the rates of dietary cholesterol absorption, tissue cholesterol content and sterol and bile salt excretion. Thirdly, we analysed the expression of genes associated with cholesterol metabolism in the liver and the intestine. We found an increase of DC numbers in the liver and in the intestine in the CD11c-hBcl2 apoE KO mice relative to control apoE KO mice. This increase of DC numbers was associated with reduced intestinal cholesterol absorption and fecal bile acid excretion, but also with greater fecal excretion of sterols. Finally, there were no differences in the cholesterol content of the intestine and the liver. Our results suggest that the decrease in plasma cholesterol level in CD11c-hBcl2 apoE KO mice relative to apoE KO mice could be due to both a decrease of intestinal cholesterol absorption and an increase in sterol excretion. The role of intestinal DCs in dietary cholesterol absorption and excretion is presently under investigation but the present study reveal that DCs are central to the atherosclerotic process, because they are implicated in cholesterol metabolism.