Abstract
NAMPT has been suggested association with atherosclerosis and insulin resistance. However, the impact of NAMPT on atherosclerosis remained unknown. Therefore, the objective of this study was to use a NAMPT loss-of-function approach to investigate the effect of NAMPT on atherosclerosis in hypercholesterolemic mice. We demonstrated that a specific NAMPT knockdown increased plasma HDL-C levels, reduced the plaque area of the total aorta en face and the cross-sectional aortic sinus, decreased macrophage number and apoptosis, and promoted RCT in HFD-fed ApoE KO mice. These changes were accompanied by increased PPARα, LXRα, ABCA1 and ABCG1 expressions in the liver. NAMPT knockdown also facilitated cholesterol efflux in RAW264.7 cells. We further investigated the effect of NAMPT knockdown on the PPARα-LXRα pathway of cholesterol metabolism with MK886 (a selective inhibitor of PPARα) in RAW264.7 macrophages. MK886 abolished the ability of NAMPT knockdown to decrease intracellular cholesterol levels to enhance the rate of 3H-cholesterol efflux and to increase ABCA1/G1 and LXRα expressions in RAW264.7 macrophages. Our observations demonstrate that NAMPT knockdown exerted antiatherogenic effects by promoting cholesterol efflux and macrophage RCT through the PPARα- LXRα- ABCA1/G1pathway in vitro and in vivo.
Highlights
Incompatible with life, with death occurring in the initial phase of embryogenesis
Sequence against Nicotinamide phosphoribosyltransferase (NAMPT) was engineered into an adenovirus vector (Ad-shNAMPT) and tested for relative silencing efficiency compared with Ad-green fluorescence protein (GFP)
In HFD-fed C57BL/6J mice, the expressions of NAMPT mRNA and protein were reduced by 55% and 25% respectively in the liver compared with normal-chow controls (Fig. 1a,c), whereas Ad- shNAMPT treatment, but not Ad-GFP, achieved a ~71% and ~57% reduction in NAMPT mRNA and protein expressions respectively in the liver
Summary
Incompatible with life, with death occurring in the initial phase of embryogenesis. The lack of knock-out mouse of NAMPT has made it difficult to systematically investigate the role of NAMPT in the development of IR and atherosclerosis. We have taken advantage of the relative tissue specificity of adenovirus for liver and the genetic specificity of shRNA-mediated RNAi to create a relative liver-specific deficiency of NAMPT expression, and examined the role of NAMPT in IR and atherosclerosis by using it to inhibit NAMPT expression in mice
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