Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

Abstract

Supplementary key words cholesterol • lipoprotein • low density lipoprotein • autotaxin • mass spectrometryLysophosphatidic acids (LPAs) are a class of small receptor active phospholipid signaling molecules that promote the growth, survival, and motility of many cell types. LPA, its receptors and enzymes involved in LPA generation and inactivation are implicated in many pathologies including cardiovascular, pulmonary, and neurological diseases, and cancer (1-3). These observations underscore the importance of identifying the sources and mechanisms regulating the bioavailability and signaling actions of LPA that underlie this association with disease processes. LPA is abundant in plasma where it is primarily generated by hydrolysis of lysophospholipids [notably lysophosphatidylcholine (LPC)] by the secreted phospholipase, autotaxin (ATX) (4, 5), and can be degraded by phospholipases and lipid phosphatases, which may contribute to turnover of circulating LPA pools (3, 4). There is significant inter-individual variability in plasma LPA levels in humans (6). Despite some provocative observations, efforts to associate plasma LPA levels with human disease risk have largely been unsuccessful (7). Plasma LPA is prominently associated with serum albumin (6). Lysophospholipids are present in HDLs and LDLs (8); and LDL, particularly oxidized LDL, contains bioactive LPA (9, 10). This association of LPA with LDL is particularly relevant to the possible role of LPA in cardiovascular disease because of the central role played by LDL in atherosclerosis. However, at present, little is known about the metabolism and function of LDL-associated LPA.Understanding the regulation of LPA metabolism and signaling in cardiovascular disease is important because, in humans, heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3), an enzyme that can Abstract Lysophosphatidic acids (LPAs) are bioactive radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. LPA metabolism and signaling are implicated in heritable risk of coronary artery disease. Genetic and pharmacological inhibition of these processes attenuate experimental atherosclerosis. LPA accumulates in atheromas, which may be a consequence of association with LDLs. The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-dependent increases in LDLassociated LPA were observed in isolated incubated plasma. ...

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

“…The extracellular LPA pool comprises distinct molecular species that differ in their acyl chain composition and binding affinity for individual LPA receptors (Yung et al, 2014). We measured LPA species in media from melanoma cells conditioned at 0, 24 and 48 hrs using LC-MS/MS (Kraemer et al, 2019) ( Figure 3A ). LPA(12:0), (16:0), (18:0), (18:1) and (20:4) were the predominant species in media containing 0.5% serum ( Figure 3B) .…”

“…LPA exists as distinct molecular species that differ in their acyl chain composition and binding affinity for individual LPA receptors (Yung et al, 2014). We measured LPA species in the respective media from melanoma cells conditioned at 0, 24 and 48 hrs by using LC-MS/MS (Kraemer et al, 2019). As shown in Fig.…”

Cross-Sectional Association between Hypercholesterolemia and Knee Pain in the Elderly with Radiographic Knee Osteoarthritis: Data from the Korean National Health and Nutritional Examination Survey

“…In addition to nociceptive pain and peripheral sensitization, evidence for neuropathic components is increasing, and it has also been reported that neuropathic pain in the hip and knee OA can be up to 23% [ 28 ]. Hypercholesterolemia increases the level of total plasma lysophosphatidic acid (LPA) [ 29 ], and an animal study by McDougall et al suggested that LPA may lead to neuropathic joint pain by causing demyelination and nerve damage [ 30 ]. Although the exact mechanism in humans is not yet well understood, it is thought that these various factors are working in combination.…”

Antibodies Against Lysophosphatidic Acid Protect Against Blast-Induced Ocular Injuries

“…The plasma samples were stored at −80 • C until analysis. LPA measurements were carried out as described earlier (43). Briefly, lipids were extracted from plasma using acidified organic solvents.…”