Niacin-induced lysosomal free cholesterol efflux via LXRα-mediated signaling pathways in macrophages retards the progression of atherosclerosis

Abstract

Background: Lysosomal free cholesterol efflux plays a crucial role in foam cell formation and atherogenesis. In addition to its lipid-modifying functions, whether the direct effect of niacin on lysosomal cholesterol efflux contributes to its anti-atherosclerotic actions remains unknown. In this study, we investigated the role of niacin in atherosclerotic lesion formation in low-density lipoprotein (LDL) receptor knockout (LDLr−/−) mice, focusing on the egress of lysosomal free cholesterol in macrophages. Methods: Aortic atherosclerotic lesions were assessed in LDLr−/− mice administered with niacin. Bone marrow-derived macrophages were cultured as a cell model. The influence of niacin on lysosomal free cholesterol efflux and the protein expression of liver X receptor α (LXRα), Niemann-Pick type C1 (NPC1), ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) were evaluated. ELISA was conducted to assess the role of niacin in interleukin (IL)-1β secretion. Results: Niacin inhibited atherosclerotic lesion formation in LDLr−/− mice; promoted lysosomal free cholesterol efflux; increased CD38 ADP-ribosylcyclase (CD38), LXRα, NPC1, ABCA1, and ABCG1 expression; enhanced nicotinic acid adenine dinucleotide phosphate synthesis; and decreased IL-1β secretion. Silencing CD38 and LXRα attenuated niacin-promoted NPC1, ABCA1, and ABCG1 expression. Silencing LXRα or NPC1 abolished the promoting effect of niacin on lysosomal free cholesterol efflux. Conclusion: The promoting effect of niacin on lysosomal free cholesterol efflux via LXRα-mediated signaling pathways may contribute to its pleiotropic anti-atherosclerotic actions.

Keywords

• Atherosclerosis
• Niacin
• Macrophage
• Lysosome
• Free cholesterol
• Liver X receptor α (LXRα)