Current Knowledge on the Biology of Lysophosphatidylserine as an Emerging Bioactive Lipid

Abstract

Lysophosphatidylserine (LysoPS) is an emerging lysophospholipid (LPL) mediator, which acts through G protein-coupled receptors, like lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). LysoPS is detected in various tissues and cells and thought to be produced mainly by the deacylation of phosphatidylserine. LysoPS has been known to stimulate degranulation of mast cells. Recently, four LysoPS-specific G protein-coupled receptors (GPCRs) were identified. These GPCRs belong to the P2Y family which covers receptors for nucleotides and LPLs and are predominantly expressed in immune cells such as lymphocytes and macrophages. Studies on knockout mice of these GPCRs have revealed that LysoPS has immune-modulatory functions. Up-regulation of a LysoPS-producing enzyme, PS-specific phospholipase A₁, was frequently observed in situations where the immune system is activated including autoimmune diseases and organ transplantations. Therefore, modulation of LysoPS signaling appears to be a promising method for providing therapies for the treatment of immune diseases. In this review, we summarize the biology of LysoPS-producing enzymes and receptors, recent developments in LysoPS signal modulators, and prospects for future therapeutic applications.

Keywords: GPCR; Immune regulation; Lysophosphatidylserine; Lysophospholipid; Phospholipase.

Fig. 1

Receptors and metabolizing enzymes for LysoPS. LysoPS is enzymatically produced from PS by PLA reaction mediated by PS-PLA₁ or ABHD16A. Produced LysoPS can activate four GPCRs, GPR34/LPS₁, P2Y10/LPS₂, LPS_2L, and GPR174/LPS₃. These LysoPS receptors are mainly expressed in the immune cells and exert a variety of immunological functions through the activation of downstream Gα proteins. LysoPS is subsequently degraded into glycerol-3-phosphoserine (GPS) and fatty acid by ABHD12, ABHD6, and PS-PLA₁

Fig. 2

Possible clinical application of LysoPS and PS-PLA₁ as a biomarker. PS-PLA₁ is the secreted enzyme and thus can be measured by ELISA in the various biological fluids. LysoPS can also be quantified using the highly sensitive LC-MS/MS system. Recent clinical studies revealed the elevated levels of LysoPS and PS-PLA₁ in the various clinical samples, suggesting the potential utility of these molecules as a potential biomarker