Signalling by lysophosphatidate and its health implications

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This issue of Essays in Biochemistry deals with lipid mediators, which are an exciting and ever-expanding series of biological molecules. Perhaps the first well-studied of such mediators were the inositol lipids whose rapid turnover was noted over 50 years ago. Since then, a huge variety of lipids and their metabolites have been characterised as lipid mediators, with many important functions in different eukaryotic organisms. In this volume we have tried to include as many notable examples as we could. The individual mediators include complex lipids (known as membrane components), intermediates in metabolism, as well as oxidised products of polyunsaturated fatty acid catabolism. The properties of many of these compounds are still being elucidated but offer important opportunities for exploitation in agriculture, industry and medicine. While the volume was being compiled, Mike Wakelam (a good friend and colleague of lipid scientists) unfortunately died prematurely from the effects of Covid-19 infection. It is our honour to dedicate this issue of Essays in Biochemistry to his memory. The cover image shows, clockwise from top left: Caterpillars eating a leaf, where jasmonic acid is secreted in defence ("Larval lepidopterans on buttonbush leaf [Newark, Ohio, USA] 1" by James St. John is licensed with CC BY 2.0); Zebrafish developing brain, showing presence of steroids (associated structure is the neurosteroid allopregnanolone), brain stained with filipin by Dr Emyr Lloyd-Evans, School of Biosciences, Cardiff University; Mouse embryo vasculature stained with PECAM, organised by S1P signalling (which is the lipid structure associated with the image) by Dr Helen Waller-Evans, Medicines Discovery Institute, Cardiff University; Healthy brain MRI with Protectin D1 (PD1) ("MRI" by jillccarlson is licensed with CC BY 2.0).

Review Article| May 26 2020

Signalling by lysophosphatidate and its health implications

Denise G. Hemmings;

Denise G. Hemmings

1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada

2Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada

3Cancer Research Institute of Northern Alberta, Women and Children’s Health Research Institute, University of Alberta, Edmonton, AB, Canada

4Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada

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David N. Brindley

0000-0003-2227-0020

David N. Brindley

3Cancer Research Institute of Northern Alberta, Women and Children’s Health Research Institute, University of Alberta, Edmonton, AB, Canada

5Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, AB, Canada

Correspondence: David N. Brindley (david.brindley@ualberta.ca)

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Author and article information

Publisher: Portland Press Ltd

Received: March 28 2020

Revision Received: May 11 2020

Accepted: May 12 2020

Online ISSN: 1744-1358

Print ISSN: 0071-1365

2020

Essays Biochem (2020) 64 (3): 547–563.

https://doi.org/10.1042/EBC20190088

Abstract

Extracellular lysophosphatidate (LPA) signalling is regulated by the balance of LPA formation by autotaxin (ATX) versus LPA degradation by lipid phosphate phosphatases (LPP) and by the relative expressions of six G-protein-coupled LPA receptors. These receptors increase cell proliferation, migration, survival and angiogenesis. Acute inflammation produced by tissue damage stimulates ATX production and LPA signalling as a component of wound healing. If inflammation does not resolve, LPA signalling becomes maladaptive in conditions including arthritis, neurologic pain, obesity and cancers. Furthermore, LPA signalling through LPA₁ receptors promotes fibrosis in skin, liver, kidneys and lungs. LPA also promotes the spread of tumours to other organs (metastasis) and the pro-survival properties of LPA explain why LPA counteracts the effects of chemotherapeutic agents and radiotherapy. ATX is secreted in response to radiation-induced DNA damage during cancer treatments and this together with increased LPA₁ receptor expression leads to radiation-induced fibrosis. The anti-inflammatory agent, dexamethasone, decreases levels of inflammatory cytokines/chemokines. This is linked to a coordinated decrease in the production of ATX and LPA_1/2 receptors and increased LPA degradation through LPP1. These effects explain why dexamethasone attenuates radiation-induced fibrosis. Increased LPA signalling is also associated with cardiovascular disease including atherosclerosis and deranged LPA signalling is associated with pregnancy complications including preeclampsia and intrahepatic cholestasis of pregnancy. LPA contributes to chronic inflammation because it stimulates the secretion of inflammatory cytokines/chemokines, which increase further ATX production and LPA signalling. Attenuating maladaptive LPA signalling provides a novel means of treating inflammatory diseases that underlie so many important medical conditions.

2020

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