title: Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages.
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.
authors.affiliation: From the Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, mathew.traini@sydney.edu.au.
authors.forename: Mathew
authors.initials: M
authors.lastname: Traini
authors.affiliation: the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Quinn
authors.affiliation: the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sandoval
authors.affiliation: From the Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139.
authors.forename: Erik
authors.initials: E
authors.lastname: Johansson
authors.affiliation: the Institute for Molecular Bioscience, University of Queensland, Queensland 4072.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: From the Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139.
authors.forename: Maaike
authors.initials: M
authors.lastname: Kockx
authors.affiliation: the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: From the Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139.
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.affiliation: From the Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, the Department of Cardiology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kritharides
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000494:pharmacology; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D009711:Nucleotides / Q000378:metabolism* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000071518:Liver X Receptors; D009711:Nucleotides; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; C469297:SMPDL3A protein, human; D013108:Sphingomyelin Phosphodiesterase
keywords: Atherosclerosis; Cholesterol; Macrophage; Metalloenzyme; Phosphodiesterases