Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages

J Biol Chem. 2014 Nov 21;289(47):32895-913. doi: 10.1074/jbc.M114.612341. Epub 2014 Oct 6.


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.

Keywords: Atherosclerosis; Cholesterol; Macrophage; Metalloenzyme; Phosphodiesterases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • CHO Cells
  • Cell Line, Tumor
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Cholesterol / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / pharmacology
  • Foam Cells / drug effects
  • Foam Cells / metabolism
  • Golgi Apparatus / metabolism
  • HEK293 Cells
  • Humans
  • Liver X Receptors
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Microscopy, Confocal
  • Nucleotides / metabolism*
  • Nucleotides / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Orphan Nuclear Receptors / metabolism
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sphingomyelin Phosphodiesterase / blood
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism*
  • Transcriptome / drug effects
  • Transcriptome / genetics


  • Liver X Receptors
  • Nucleotides
  • Orphan Nuclear Receptors
  • Cholesterol
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • SMPDL3A protein, human
  • Sphingomyelin Phosphodiesterase