Abstract
Although simple in structure, lysophosphatidic acid (LPA) is a potent bioactive lipid that profoundly influences cellular signaling and function upon binding to G protein-coupled receptors (LPA1-6). The majority of circulating LPA is produced by the secreted enzyme autotaxin (ATX). Alterations in LPA signaling, in conjunction with changes in autotaxin (ATX) expression and activity, have been implicated in metabolic and inflammatory disorders including obesity, insulin resistance, and cardiovascular disease. This review summarizes our current understanding of the sources and metabolism of LPA with focus on the influence of diet on circulating LPA. Furthermore, we explore how the ATX-LPA pathway impacts obesity and obesity-associated disorders, including impaired glucose homeostasis, insulin resistance, and cardiovascular disease.
Highlights
Apart from serving as integral constituents of cellular membranes and sources of energy, lipids can play an important role as signaling molecules
Targeting the ATX-lysophosphatidic acid (LPA)-LPA1-6 pathway holds therapeutic potential, as this signaling axis may promote the development of metabolic disorders through multiple mechanisms involving inflammation, fibrosis, and impaired mitochondrial function and PPARγ activation
At least three LPA receptor antagonists are in clinical trials [131], while many more LPA receptor modulators have been developed or are in development [132]
Summary
Apart from serving as integral constituents of cellular membranes and sources of energy, lipids can play an important role as signaling molecules. The diversity of cellular responses to LPA is likely mediated by distinct LPA receptor tissue expression patterns, receptor–ligand kinetics, and substrate/acyl chain specificity of LPA. IIA secretory phospholipase A2 ; mPA-PLA1 , membrane-bound PA-selective phospholipase A1 ; LCAT, lecithin–cholesterol acyltransferase In addition to their potential tissue-specific expression, LPA receptors show differences in receptor–ligand kinetics. LPA3 prefers 2-acyl-LPA species; only unsaturated LPAs appear to be ligands for this receptor [18,20,21]. Dynamic changes in LPA species in different biological fluids could favor the activation of specific LPA receptors. LPA species are ester-linked and contain 16:0, 18:0, 18:1, 18:2, and 20:4 acyl chains, at concentrations ranging from 10–100 nM [24]. The distribution of 1- versus 2-acyl LPA species in biological fluids is unknown; future studies should aim to discriminate between these LPA species and examine their role in physiological and pathological processes
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