Excess nitric oxide impairs liver X receptor α-ATP-binding cassette transporter A1-dependent cholesterol efflux in macrophage foam cells

Abstract

Excess nitric oxide (NO) promotes the progression of atherosclerosis by increasing the oxidation of low-density lipoprotein (LDL) and inflammatory responses. However, little is known about the impact of NO and its underlying molecular mechanism on lipid metabolism of macrophage foam cells. In this study, Oil-red O staining, cholesterol and triglyceride assay, Dil-oxidized LDL (oxLDL) binding assay, cholesterol efflux assay, real-time RT-PCR and Western blot analysis were used for in vitro experiments. Apolipoprotein E-deficient (apoE(-/-) ) and apoE and inducible nitric oxide synthase-deficient (apoE(-/-) iNOS(-/-) ) mice were as our in vivo models. Treatment with S-nitroso-N-acetyl-D,L-penicillamine (SNAP), an NO donor, exacerbated oxLDL-induced cholesterol accumulation in macrophages, because of reduced efficacy of cholesterol efflux. In addition, SNAP decreased the protein level of ATP-binding cassette transporter A1 (ABCA1) without affecting scavenger receptor type A (SR-A), CD36, ABCG1, or SR-B1 levels. This SNAP-mediated downregulation of ABCA1 was mainly through the effect of NO but not peroxynitrite. Furthermore, the SNAP-downregulated ABCA1 was due to the decrease in the liver X receptor α (LXRα)-dependent transcriptional regulation. Moreover, genetic deletion of iNOS increased the serum capacity of reverse cholesterol efflux and protein expression of LXRα, ABCA1, and SR-BI in aortas and retarded atherosclerosis in apoE(-/-) mice. Our findings provide new insights in the pro-atherogenic effect of excess NO on cholesterol metabolism in macrophages.

Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis

“…Cholesterol homoeostasis of foam cells is tightly controlled by SR-mediated cholesterol internalization and RCT-mediated cholesterol efflux (Viñals et al 2005, Rader 2006, Lee et al 2009, Lin et al 2011, 2012. Here, we demonstrate that the YC-1 suppression of foam cell formation caused by the upregulation of ABCA1, which is consistent with previous studies showing that upregulation of ABCA1 mitigates cholesterol accumulation in foam cells (Lu et al 2010, Cheng et al 2011, Zhao et al 2013b, 2014. ABCA1 is the major type of RCT responsible for cholesterol efflux in macrophages.…”

Association of liver X receptor α (LXRα) gene polymorphism and ischemic stroke

“…In addition, LXRa can inhibit many inflammatory cytokines and the expression of chemokines (Zhang et al, 2001;Watanabe et al, 2013;Jin et al, 2013;Chen et al, 2013;Zhao et al, 2014). All of these functions indicate that the LXRa signaling pathway plays an important role in the development of atherosclerosis and ischemic stroke.…”

Association of liver X receptor α (LXRα) gene polymorphism and coronary heart disease, serum lipids and glucose levels

“…The regulation function of activated LXR α was as follows: 1) it can mediate the binding and transporting factor Al (ABCAl), ABCGl, ABCG5, ABCG4, ABCG8 located in the human macrophages and small intestine target genes ATP to promote endogenous lipid membrane transport; 2) it can activate human macrophages Niemann - Pick Cl protein (NPCI) and C2 protein (NPC2) to promote cholesterol transport from endosomes chamber to the cytoplasmic membrane; 3) it can promote receptor ApoE, ApoC-I, C-II, C-IV expression which were in charge of regulating the cholesterol outflow in adipocytes and macrophages; 4) it can control the liver and macrophages regulating enzymes such as phospholipid transfer protein (PLTP), lipoprotein lipase (LPL) remodeling lipoproteins. Meanwhile LXR α can inhibit many inflammatory cytokines and the expression of chemokines [14-18]. All these indicated that LXR α signaling pathway played an important role in the development of atherosclerosis.…”