Lysophospholipids in laboratory medicine

Abstract

Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as second-generation lipid mediators. In our laboratory, the functional roles of these lipid mediators and the mechanisms by which the levels of these mediators are regulated in vivo have been studied. Based on these studies, the clinical introduction of assays for LPLs and related proteins has been pursued and will be described in this review. Although assays of these lipids themselves are possible, autotaxin (ATX), apolipoprotein M (ApoM), and phosphatidylserine-specific phospholipase A₁ (PS-PLA₁) are more promising as alternate biomarkers for LPA, S1P, and LysoPS, respectively. Presently, ATX, which produces LPA through its lysophospholipase D activity, has been shown to be a useful laboratory test for the diagnosis and staging of liver fibrosis, whereas PS-PLA₁ and ApoM are considered to be promising clinical markers reflecting the in vivo actions induced by LysoPS and S1P.

Keywords: apolipoprotein M; autotaxin; lysophosphatidic acid; lysophosphatidylserine; lysophospholipids; sphingosine 1-phosphate.

Figure 1.

The three major LPLs: LPA, S1P, and LysoPS. The production and actions of these lipid mediators are illustrated. Although the mechanisms by which these bioactive lipids are formed differ, they act on specific GPCRs expressed on the cell surface, resulting in a variety of cellular responses. See the text for details.

Figure 2.

LPA metabolism in the blood. In plasma, LPA is produced by the lysoPLD activity of ATX from substrate LPLs. LPC is the most important substrate; sn-1 acyl LPC is shown in the figure. The product LPA undergoes dephosphorylation by the action of the ectoenzyme LPP, resulting in the formation of monoacylglycerol (MAG).

Figure 3.

Regulation of the ATX level and resultant LPA production in the blood. Although ATX is expressed in a variety of cells and tissues, the main source of ATX in the bloodstream is considered to be adipose tissue. The placenta produces ATX, and the serum ATX level in normal pregnant women is positively correlated with the gestational week; the serum ATX antigen level of patients with PIH is lower than that of normal pregnant women. As for malignancy, the serum ATX level is increased in follicular lymphoma and may be a promising marker for this B-cell lymphoma. ATX was cloned from the supernatant of melanoma cells, and serum ATX is reportedly elevated in patients with melanoma, but only in progressive cases. Serum ATX activity may be useful for identifying pancreatic cancer when used together with other serum markers of pancreatic cancer. The liver seems to be important for the regulation of blood ATX by its clearance from the circulation by scavenger receptors on liver sinusoidal endothelial cells; serum ATX is increased in chronic liver disease, possibly because of the reduction of ATX clearance by the liver. In most cases, changes in serum ATX are accompanied by parallel variations in plasma LPA. The only exception seems to be ACS; only the plasma LPA level, and not the serum ATX level, increases in patients with ACS. See the text for details.

Figure 4.

Carrier-dependent effects of S1P in atherosclerosis. At least part of the HDL pleiotropic effects are thought to be due to S1P present on HDL, and HDL-associated S1P is bound specifically to ApoM. ApoM is not just a carrier of S1P, but is also an important modifier that increases the total amount of S1P in the body by protecting S1P from degradation. Furthermore, ApoM strengthens the agonist properties of S1P toward S1P₁, which is anti-atherosclerotic, while it weakens the agonist properties for S1P₂, which is pro-atherosclerotic. On the other hand, S1P bound to albumin preferably interacts with S1P₂.