Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

Abstract

Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.

Identification of ABHD6 as a regulator of lysophosphatidylserines in the mammalian liver and kidneys

“…Specifically, in the central nervous system, lyso-PS controls the activation of microglial cells, and in turn neuroinflammation, particularly in the cerebellum. On the other hand, in the immune system, this signaling lysophospholipid regulates histamine release from mast cell degranulation, pro-inflammatory responses from macrophages, and the maturation of T cells, to list a few processes 1, 2 . While it is now evident that lyso-PS is ubiquitously present 1 , little remains known on how it is enzymatically produced and metabolized, or what are its physiological functions in other (peripheral) mammalian tissues.…”

“…Our studies partly corroborate these findings, and show that ABHD6 functions as a lyso-PS-specific lysophospholipase in the liver and kidney in mice, and selectively controls levels of lyso-PS lipids, but not other lysophospholipids, in these tissues under normal physiological conditions (not in high-fat diet paradigms) ( Figure 3 , Supplementary Figure 2 ). Given its recent links to systemic (glucose) metabolism 1 , it will be interesting to see how dysregulated lyso-PS signaling in the liver might contribute towards metabolic conditions such as hepatic steatosis or systemic insulin resistance (modulated by ABHD6 activity), and crosstalk with other lipid pathways involved in such human diseases.…”

“…Given its amphiphilic (hydrophilic and lipophilic) chemical nature, lyso-PS acts as a very potent hormone-like signaling molecule 11 . Hence, the physiological concentrations of lyso-PS are tightly regulated by dedicated enzymes in all mammalian tissues 1, 2 . For example, lyso-PS is biosynthesized from phosphatidylserine (PS) precursors by the action of PS-specific phospholipases.…”

“…The glycerolysophospholipid lysophosphatidylserine (lyso-PS) is fast emerging as an important signaling lipid, which is central to the functioning of many important biological processes in mammals, including humans 1,2 . Given its indispensable role in physiology, over the past two decades, the biochemical activities and mechanisms associated with lyso-PS metabolism and signaling have been extensively investigated, mostly in the context of the mammalian central nervous and immune system 1,2 . This study bias stems from numerous genetic mapping of human subjects (patients) or population-level genome-wide association studies, which causally link the dysregulation in lyso-PS metabolism or signaling to an array of hereditary neurological and autoimmune diseases in humans 1,[3][4][5][6][7][8][9][10] .…”

“…Given its indispensable role in physiology, over the past two decades, the biochemical activities and mechanisms associated with lyso-PS metabolism and signaling have been extensively investigated, mostly in the context of the mammalian central nervous and immune system 1,2 . This study bias stems from numerous genetic mapping of human subjects (patients) or population-level genome-wide association studies, which causally link the dysregulation in lyso-PS metabolism or signaling to an array of hereditary neurological and autoimmune diseases in humans 1,[3][4][5][6][7][8][9][10] . Despite this, it is now apparent from several recent reports that lyso-PS is quite abundant in almost all mammalian tissues 1 , and yet, very little remains known of its physiological role or metabolism beyond the human nervous and immune systems.…”