Niacin‐induced enhancement of lysosomal cholesterol efflux in macrophages through CD38 ‐ NAADP signaling pathway: implication in reduced foam cell formation (671.6)

Niacin (Nicotinic acid), a hyperlipidemia‐lowering agent, acts as a substrate in the enzymatic synthesis of lysosomal Ca 2+ messenger, NAADP by CD38. Our recent studies have demonstrated that the deficiency of CD38 led to lysosomal lipid accumulation in macrophages, foam cell formation and atherosclerosis, as observed in CD38 ‐/‐ mice. The present study was designed to examine the effects of niacin on the foam cell formation and explore the underlying mechanisms. Using fluorescent microplate reader and confocal microscope, we found that niacin dose‐dependently (in mM: 0, 0.05, 0.1, 0.3, 1 and 2) decreased lysosomal lipid accumulation in bone marrow‐derived wild type macrophages treated with oxLDL (40 µg/ml) as stained by lysosomal lipid specific dye of Bodipy 493/503, but it had no effects in CD38 ‐/‐ macrophages. This niacin‐induced lysosomal lipid lowering effects were almost completely abolished by NAADP antagonist of PPADS (100 µM). In the niacin‐treated macrophages, the cholesterol level in the purified lysosomal fractions was markedly decreased. Correspondingly, oil red o staining and electron microscope assay showed that the foam cell formation was significantly reduced. These results for the first time reveal that niacin promotes lysosomal cholesterol efflux and thereby attenuates macrophage foam cell formation, which is associated with activation of CD38‐NAADP signaling pathway. Grant Funding Source : NIH R01HL115068 and R01HL091464