Abstract
Cholesterol-loaded foam cell macrophages are prominent in atherosclerotic lesions and play complex roles in both inflammatory signaling and lipid metabolism, which are underpinned by large scale reprogramming of gene expression. We performed a microarray study of primary human macrophages that showed that transcription of the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene is up-regulated after cholesterol loading. SMPDL3A protein expression in and secretion from primary macrophages are stimulated by cholesterol loading, liver X receptor ligands, and cyclic AMP, and N-glycosylated SMPDL3A protein is detectable in circulating blood. We demonstrate for the first time that SMPDL3A is a functional phosphodiesterase with an acidic pH optimum. We provide evidence that SMPDL3A is not an acid sphingomyelinase but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH. SMPDL3A is a major source of nucleotide phosphodiesterase activity secreted by liver X receptor-stimulated human macrophages. Extracellular nucleotides such as ATP may activate pro-inflammatory responses in immune cells. Increased expression and secretion of SMPDL3A by cholesterol-loaded macrophage foam cells in lesions may decrease local concentrations of pro-inflammatory nucleotides and potentially represent a novel anti-inflammatory axis linking lipid metabolism with purinergic signaling in atherosclerosis.
Highlights
Cholesterol-loaded macrophages are key mediators of atherosclerosis and demonstrate increased sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) expression and secretion
SMPDL3A Expression and Secretion Is Up-regulated by Cholesterol Loading and liver X receptor (LXR) Agonists in Primary Human Macrophages—To identify genes differentially regulated in human macrophages by cholesterol accumulation, oligonucleotide microarray analysis was performed on human monocyte-derived macrophages (HMDMs) obtained from two separate donors Ϯ cholesterol loading by incubation with acetylated LDL (AcLDL) for 48 h
Our microarray study of cholesterol-loaded primary human macrophages led to the identification of SMPDL3A as a novel cholesterol-regulated gene, and we present the first experimental evidence of an enzymatic activity for this protein
Summary
Cholesterol-loaded macrophages are key mediators of atherosclerosis and demonstrate increased SMPDL3A expression and secretion. Increased expression and secretion of SMPDL3A by cholesterolloaded macrophage foam cells in lesions may decrease local concentrations of pro-inflammatory nucleotides and potentially represent a novel anti-inflammatory axis linking lipid metabolism with purinergic signaling in atherosclerosis. SMPDL3A was originally identified as a gene up-regulated in bladder tumor versus healthy urothelium tissue [7], and more recently it has been shown to be regulated by liver X receptor (LXR) ligands in human macrophage cell lines [8, 9]. We show that SMPDL3A is the major nucleotide phosphodiesterase secreted by human THP-1 macrophages after LXR stimulation This unexpected activity, together with its up-regulation in cholesterol-loaded macrophages, indicates the regulation and enzymology of SMPDL3A are distinct from aSMase and may play a novel role in the pathobiology of atherosclerosis
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