Niacin promotes the efflux of lysosomal cholesterol from macrophages via the CD38/NAADP signaling pathway. Issue 12 (June 2022)

• Record Type: Journal Article
• Authors: Yang, Shenghua; Zhang, Fan; Li, Quanwen; Li, Quanzhong
• Is Part Of: Experimental biology and medicine. Volume 247:Issue 12(2022)
• Page Start: 1047
• Page End: 1054
• Publication Date: 2022-06
• Subjects: Niacin -- cholesterol -- lysosome -- atherosclerosis -- cluster of differentiation 38/nicotinic acid adenine dinucleotide phosphate -- low-density lipoprotein receptor −/− mice; Physiology -- Periodicals; Biology, Experimental -- Periodicals; Medicine, Experimental -- Periodicals; 610.72
• DOI: 10.1177/15353702221084632
• Languages: English
• ISSNs: 1535-3702

Abstract

The accumulation of free cholesterol in macrophage lysosomes significantly enhances atherogenesis. Our recent study demonstrated that the cluster of differentiation 38 (CD38)/nicotinic acid adenine dinucleotide phosphate (NAADP)/Ca 2+ signaling pathway plays a critical role in the efflux of lysosomal free cholesterol from macrophages in atherosclerosis. Niacin, known as nicotinic acid, is one of the oldest lipid-lowering medications showing unique anti-atherosclerotic activity. However, it is unknown whether this anti-atherosclerosis activity is associated with the efflux of lysosomal compartmentalized cholesterol in macrophages. In this study, we investigated the anti-atherosclerotic effects of niacin on the reduction of lysosomal free cholesterol via CD38/NAADP signaling in macrophages derived from low-density lipoprotein receptor (LDLr −/− ) mice. Fluorescent filipin and Nile red labeling coupled with confocal microscopy demonstrated that niacin reduced free cholesterol accumulation in lysosomes in a concentration-dependent manner. Transmission electron microscopy also showed that niacin markedly decreased cholesterol crystal formation in lysosomes in oxidized LDL-containing LDLr −/− bone marrow–derived macrophages. Enzyme-linked immunosorbent assays showed that niacin increased NAADP production in a concentration-dependent manner, which was inhibited by small interfering RNA interference of CD38. Therefore, niacin may promote the efflux of lysosomal cholesterol from macrophages via the CD38/NAADP signaling pathway.