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

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 LDL-associated LPA were observed in isolated incubated plasma. ATX acted directly on LDL-associated lysophospholipid substrates in vitro. LDL from all human subjects examined contained LPA and was decreased by lipid-lowering drug therapies. Human and mouse plasma therefore contains a diet-sensitive LDL-associated LPA pool that might contribute to the cardiovascular disease-promoting effects of LPA. 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 LDL-associated LPA were observed in isolated incubated plasma. ATX acted directly on LDL-associated lysophospholipid substrates in vitro. LDL from all human subjects examined contained LPA and was decreased by lipid-lowering drug therapies. Human and mouse plasma therefore contains a diet-sensitive LDL-associated LPA pool that might contribute to the cardiovascular disease-promoting effects of LPA. Lysophosphatidic 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 (1Hisano Y. Hla T. Bioactive lysolipids in cancer and angiogenesis.Pharmacol. Ther. 2019; 193: 91-98Crossref PubMed Scopus (52) Google Scholar, 2Herr D.R. Chew W.S. Satish R.L. Ong W.Y. Pleotropic roles of autotaxin in the nervous system present opportunities for the development of novel therapeutics for neurological diseases.Mol. Neurobiol. July 30, 2019; (Epub ahead of print. doi:10.1007/s12035-019-01719-1.)Google Scholar, 3Benesch M.G.K. MacIntyre I.T.K. McMullen T.P.W. Brindley D.N. Coming of age for autotaxin and lysophosphatidate signaling: clinical applications for preventing, detecting and targeting tumor-promoting inflammation.Cancers (Basel). 2018; 10: E73Crossref PubMed Scopus (50) Google Scholar). 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) (4Aoki J. Inoue A. Okudaira S. Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518Crossref PubMed Scopus (347) Google Scholar, 5Aoki J. Taira A. Takanezawa Y. Kishi Y. Hama K. Kishimoto T. Mizuno K. Saku K. Taguchi R. Arai H. Serum lysophosphatidic acid is produced through diverse phospholipase pathways.J. Biol. Chem. 2002; 277: 48737-48744Abstract Full Text Full Text PDF PubMed Scopus (361) Google Scholar), and can be degraded by phospholipases and lipid phosphatases, which may contribute to turnover of circulating LPA pools (3Benesch M.G.K. MacIntyre I.T.K. McMullen T.P.W. Brindley D.N. Coming of age for autotaxin and lysophosphatidate signaling: clinical applications for preventing, detecting and targeting tumor-promoting inflammation.Cancers (Basel). 2018; 10: E73Crossref PubMed Scopus (50) Google Scholar, 4Aoki J. Inoue A. Okudaira S. Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518Crossref PubMed Scopus (347) Google Scholar). There is significant inter-individual variability in plasma LPA levels in humans (6Michalczyk A. Budkowska M. Dolegowska B. Chlubek D. Safranow K. Lysophosphatidic acid plasma concentrations in healthy subjects: circadian rhythm and associations with demographic, anthropometric and biochemical parameters.Lipids Health Dis. 2017; 16: 140Crossref PubMed Scopus (34) Google Scholar). Despite some provocative observations, efforts to associate plasma LPA levels with human disease risk have largely been unsuccessful (7Yagi T. Shoaib M. Kuschner C. Nishikimi M. Becker L.B. Lee A.T. Kim J. Challenges and inconsistencies in using lysophosphatidic acid as a biomarker for ovarian cancer.Cancers (Basel). 2019; 11: E520Crossref PubMed Scopus (17) Google Scholar). Plasma LPA is prominently associated with serum albumin (6Michalczyk A. Budkowska M. Dolegowska B. Chlubek D. Safranow K. Lysophosphatidic acid plasma concentrations in healthy subjects: circadian rhythm and associations with demographic, anthropometric and biochemical parameters.Lipids Health Dis. 2017; 16: 140Crossref PubMed Scopus (34) Google Scholar). Lysophospholipids are present in HDLs and LDLs (8Rauschert S. Gazquez A. Uhl O. Kirchberg F.F. Demmelmair H. Ruiz-Palacios M. Prieto-Sanchez M.T. Blanco-Carnero J.E. Nieto A. Larque E. et al.Phospholipids in lipoproteins: compositional differences across VLDL, LDL, and HDL in pregnant women.Lipids Health Dis. 2019; 18: 20Crossref PubMed Scopus (14) Google Scholar); and LDL, particularly oxidized LDL, contains bioactive LPA (9Siess W. Zangl K.J. Essler M. Bauer M. Brandl R. Corrinth C. Bittman R. Tigyi G. Aepfelbacher M. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions.Proc. Natl. Acad. Sci. USA. 1999; 96: 6931-6936Crossref PubMed Scopus (369) Google Scholar, 10Zhou Z. Subramanian P. Sevilmis G. Globke B. Soehnlein O. Karshovska E. Megens R. Heyll K. Chun J. Saulnier-Blache J.S. et al.Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium.Cell Metab. 2011; 13: Full Text Full Text PDF PubMed Scopus Google Scholar). association of LPA with LDL is particularly to the of LPA in cardiovascular disease of the by LDL in atherosclerosis. is the metabolism and of LDL-associated LPA. the of LPA metabolism and signaling in cardiovascular disease is in heritable of the gene encoding lipid that can and LPA, are associated with inter-individual variability in coronary artery disease risk M. S. C. D. G. in 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). The that that attenuated inactivation of LPA signaling may underlie increased risk of coronary artery disease A. M. C. R. of in and in Full Text Full Text PDF PubMed Scopus Google Scholar, K.J. D. in human a coronary artery that through 11: PubMed Scopus Google Scholar, G. of gene by Biol. Chem. July 30, 2019; ahead of Full Text Full Text PDF Scopus Google Scholar). LPA activation of cell receptors D.R. Chun J. Lysophosphatidic acid signaling and disease PubMed Scopus Google Scholar). LPA receptors are by and endothelial cells A. Lysophospholipids in coronary artery and PubMed Scopus Google Scholar). The and actions of LPA are a of LPA effects on of the endothelial cell and of and of Z. Subramanian P. Sevilmis G. Globke B. Soehnlein O. Karshovska E. Megens R. Heyll K. Chun J. Saulnier-Blache J.S. et al.Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium.Cell Metab. 2011; 13: Full Text Full Text PDF PubMed Scopus Google Scholar, D.R. Chun J. Lysophosphatidic acid signaling and disease PubMed Scopus Google Scholar, M. LPA from cells and J. PubMed Scopus Google Scholar, W. Tigyi G. and of lysophosphatidic PubMed Scopus Google Scholar, P. S. A. in the PubMed Scopus (17) Google Scholar, E. K. and mechanisms of PubMed Scopus Google Scholar, H. R. Y. A. R. G. T. E. S. et acid of in endothelial Biol. PubMed Scopus Google Scholar, E. T. M. J. of lysophosphatidic acid receptors and atherosclerosis development in PubMed Scopus Google Scholar, P. the for the in the development and of Biol. PubMed Scopus Google Scholar). LPA accumulates in human and mouse (9Siess W. Zangl K.J. Essler M. Bauer M. Brandl R. Corrinth C. Bittman R. Tigyi G. Aepfelbacher M. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions.Proc. Natl. Acad. Sci. USA. 1999; 96: 6931-6936Crossref PubMed Scopus (369) Google Scholar, T. K. R. K. M. Kishimoto T. M. T. A. et lysophosphatidic acid levels in coronary of with coronary Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Lysophosphatidic acid atherosclerotic by Full Text Full Text PDF PubMed Scopus Google Scholar), and mice with deficiency or pharmacological of LPA receptors are from atherosclerosis Z. Subramanian P. Sevilmis G. Globke B. Soehnlein O. Karshovska E. Megens R. Heyll K. Chun J. Saulnier-Blache J.S. et al.Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium.Cell Metab. 2011; 13: Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. D. A. J.S. et on the small to and by Western and lysophosphatidic Full Text Full Text PDF PubMed Scopus Google Scholar). that are associated with of LPA metabolism and in the LDL mouse of a high-fat Western in increased levels of LPA that promote and M. G. D. A. J.S. et on the small to and by Western and lysophosphatidic Full Text Full Text PDF PubMed Scopus Google Scholar). knockout of the ENPP2 gene encoding ATX that ATX to circulating LPA levels in high-fat diet-fed mice R. C. S. E. A. C. P. Saulnier-Blache J.S. Adipose-specific of autotaxin and plasma lysophosphatidic 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, H. T. S. J. M. H. et and its lysophosphatidic acid and promote in PubMed Scopus Google Scholar). is for a of LPA in hyperlipidemia and its including atherosclerosis and K. C. P. D. M. et signaling to in and 2018; Full Text Full Text PDF PubMed Scopus (34) Google Scholar). the and LPA in mouse of the levels and of LPA associated with plasma lipoprotein pools and examined the of ATX in regulating LDL-associated LPA. that a high-fat in with genetically hyperlipidemia in LDL-associated LPA in and that ATX can directly on LDL-associated lysophospholipids to LPA. These observations to humans LPA was associated with LDL in plasma from all human subjects a of these lipid-lowering drug decreased this pool of circulating LDL-associated LPA. These a for ATX in the generation of a diet-sensitive LDL-associated LPA pool and the that LDL-associated LPA in cardiovascular disease processes. The and the all and the mice were in a and with and the effects of hyperlipidemia on plasma LPA plasma from mice with genetically hyperlipidemia fed the high-fat Western were with mice fed a normal Plasma were from wild-type or mice with the activated of or normal or a Western for is a in which of the from of the by by and by convertase subtilisin/kexin type were by a of of a of The of ATX was by plasma from ENPP2 mice in of ATX in These mice were with the activated and fed the high-fat Western for M. J. S. M. autotaxin and associated with 2019; Scopus Google Scholar). was as ATX activity was in which was for human plasma was from subjects in as of the of or were as from of the of lipid-lowering plasma were from subjects to and of was from these subjects and the to the in the of of plasma from mice or from human subjects were by using a to system using from and for lipoprotein of mouse plasma Full Text Full Text PDF PubMed Google Scholar). The was and with a of The was a using We and the of was The were using Western with or serum albumin to LDL, VLDL, or serum plasma were for or and for LPA as were to LDL from human plasma to LPA associated with LDL S. B. J. J. for the of 18: PubMed Scopus Google Scholar). LPA of LDL was in a of human plasma with a of LDL of was with of plasma. The was incubated for and for were from the and and LPA as LPA were using from S. of lysophosphatidic acid and by Biol. 2018; PubMed Scopus Google Scholar). of plasma or of plasma were using the were to and for of LPA were in as LPA was using a with in were on a with for were as for for for for for for for for for for for for for for for for for and for were using and LPA concentrations were using the as a plasma was using a plasma was with a The was from a human The was and a to a The was cells and was isolated and to cells to The was to secreted in cells was by using was and by for and by through a The was using a and system to and or The was a and the was with of and The was with a to The were and in and was and of were in and The of the was by and by Western for concentrations were by The activity of the was to that by and J. S. E. J.E. T. Z. et of and by Biol. 2011; 18: PubMed Scopus Google Scholar). of isolated human LDL of were incubated for with human in from A. E. S. C. The of autotaxin activity is for mouse 10: PubMed Scopus (50) Google and for of LPA. The ATX of increases in LPA was by including a ATX in the was as to activity of the human and activity was by of LPA. ATX activity in mouse plasma was by plasma from mice fed the high-fat Western for for and the plasma by and LPA associated with by was by with LPA for was incubated with or isolated human LDL These incubated plasma were by to LDL from were from the and LPA by The in the and were using are in the and the We the effects of and genetically hyperlipidemia on circulating LPA by plasma LPA levels from mouse plasma using and plasma LPA using were wild-type and genetically mice fed or Western We plasma using to the levels of LPA associated with or wild-type mice fed a Western for increased primarily to a in Western diet-fed wild-type mice in plasma LPA of increased LPA mice that are genetically mice or mice activated which is a that the and plasma was to LDL-associated plasma LPA was was to and LPA mice LPA which is from the increases in LPA associated with lipoprotein pools observed in and activated There were significant diet-dependent differences in the of LPA associated with albumin of the experimental of mice that as is from and is significant inter-individual variability in plasma LPA levels mice with the fed the Despite this that the Western increased LDL-associated LPA was in differences in levels and distribution of plasma LPA in activated and mice. of LPA from plasma or of plasma by plasma are as of LPA associated with LDL HDL or albumin LPA the of all LPA were by increases in high-fat Western diet-fed LPA in the from mice fed the or Western were by LPA in the from mice fed the or Western were by LPA in the from mice fed the or Western were by of mouse LPA associated with LDL in mice of the fed or high-fat Western are as the in in LPA in the from mice fed the or Western were by in a of mouse LPA associated with LDL in mice of the fed or high-fat Western are as the in in LDL and in the development and of on the for that LDL-associated LPA is increased in mice fed the high-fat Western LDL levels are by deficiency or of activated activated wild-type mice or mice the Western LPA were in We observed significant increases in and LPA, with the observed and We that this in LPA is largely by ATX mice that have ATX in M. J. S. M. autotaxin and associated with 2019; Scopus Google and LDL-associated LPA fed the Western for that LDL and levels in these mice were from wild-type mice that in to high-fat are M. J. S. M. autotaxin and associated with 2019; Scopus Google Scholar). LPA was in HDL and albumin from levels observed in wild-type mice activated these differences that for mice from to a with from increases in plasma LPA pools levels of the LPA present in plasma from a high-fat Western diet-fed activated of all LPA present in the plasma lipoprotein pools isolated from activated high-fat Western diet-fed mice with LPA levels in plasma from activated Western diet-fed wild-type mice of levels of the LPA in plasma LDL isolated from high-fat Western diet-fed activated wild-type mice or from Western diet-fed activated by We were in in mice have to We human plasma from with plasma levels to LPA be in We with significant by plasma and LDL-associated a association with plasma LPA and LDL-associated LPA. LDL isolated from all subjects contained levels of LPA. of this association LDL and LPA, to LDL-associated LPA be to lipid-lowering We subjects and Plasma from subjects and of were by to of the LPA of lipoprotein LPA was in LDL from to of lipid-lowering this LPA pool was in all subjects of lipid-lowering are for plasma and significant LDL-associated LPA in the We a of in a plasma plasma from the of with LDL-associated plasma of LPA were in plasma or isolated lipoprotein from and of lipid-lowering drug of plasma were and LPA levels in plasma or the lipoprotein are to this in a of LPA were in plasma or isolated lipoprotein from and of lipid-lowering drug of plasma were and LPA levels in plasma or the lipoprotein are to this in LDL-associated LPA were on ATX in mice. this might from hydrolysis of LDL-associated lysophospholipid generated and that this activity with the ATX the to activity LDL-associated substrates with isolated human LDL for in the of LPA was increased The ATX this in LPA. is that plasma in ATX-dependent increases in plasma LPA (4Aoki J. Inoue A. Okudaira S. Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518Crossref PubMed Scopus (347) Google Scholar). the that ATX in plasma can directly on LDL-associated incubated plasma from high-fat Western diet-fed mice and the incubated plasma to increases in LPA of plasma in increases in the LPA of all of the lipoprotein including LDL, that ATX can directly on LDL-associated substrates in plasma. of plasma in a in serum LPA. We were therefore in the that serum LPA to LDL in plasma. We therefore incubated with LPA with isolated LDL, the by and LDL-associated LPA. these LPA with a of and incubated this with LDL a of a of the LPA was associated with The of these is of LPA from serum albumin to LDL can in this is to for the rapid and ATX-dependent increases in LDL-associated LPA observed in incubated plasma. that levels of the gene encoding that can and LPA are associated with heritable cardiovascular disease risk in humans K.J. D. in human a coronary artery that through 11: PubMed Scopus Google Scholar). efforts to LPA as a of cardiovascular disease and the that circulating LPA be a biomarker of cardiovascular disease We that can the levels of LPA associated with circulating in and that a high-fat in with of LDL can LDL-associated LPA in plasma. We that ATX is for these of plasma LPA. that ATX can directly on LDL-associated lysophospholipid These that ATX may directly LPA of circulating LDL and that a on the plasma distribution of LPA that may in signaling and associated disease in plasma LPA have been associated with and disease that plasma LPA be a biomarker of these in humans J. R. Y. S. Z. W. B. Plasma of Health Dis. 2019; 18: PubMed Scopus Google Scholar, J. S. Y. P. acid signaling mediates in mice and human 2019; PubMed Scopus Google Scholar). have to LPA that with the of diseases, as and cancer J. R. Y. S. Z. W. B. Plasma of Health Dis. 2019; 18: PubMed Scopus Google Scholar, S. 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W. of lysophosphatidic acid receptors activation by the lipid of atherosclerotic PubMed Scopus Google Scholar, M. R. Saulnier-Blache J.S. S. lysophosphatidic acid to its J. Full Text Full Text PDF PubMed Scopus Google Scholar). mouse that mouse and human LDL many of the LPA to be increased in the plasma of humans and that in atherosclerotic that and were the abundant LDL-associated LPA the that these LPA might contribute to disease risk associated with circulating LDL and have been to be associated with circulating LPA levels T. K. R. K. M. Kishimoto T. M. T. A. et lysophosphatidic acid levels in coronary of with coronary Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. Y. P. acid signaling mediates in mice and human 2019; PubMed Scopus Google Scholar, C. Serum lysophosphatidic acid concentrations by in with J. 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The mechanisms for these associations plasma LPA levels and in humans are that levels and distribution of LPA in plasma are by high-fat in mouse to contribute to inter-individual variability in plasma LPA levels in that in mice these diet-dependent in LDL-associated LPA ATX The in LDL-associated LPA in ATX knockout mice might contribute to the and observed by in ATX knockout mice C. R. K. S. C. Saulnier-Blache J.S. of acid signaling in and 96: PubMed Scopus Google Scholar, S. M. Okudaira S. J. T. R. K. K. H. K. et to and in PubMed Scopus Google Scholar). observations of LDL-associated LPA in mice to humans LPA was present in LDL from all subjects of human plasma to and of lipid-lowering the that lipid this LDL-associated LPA in LPA plasma by plasma or are to these LPA in humans and LPA or pools of LPA with cardiovascular of the of plasma LPA LPA as a hyperlipidemia and cardiovascular disease. We and have that LPA is associated with serum albumin in plasma from wild-type mice fed a normal J.E. The of lysophospholipids to and J. PubMed Scopus Google Scholar, G. R. to serum albumin in and in Biol. Chem. Full Text PDF PubMed Google Scholar). in that LPA is is the signaling of LPA be by association with and lipid G. R. to serum albumin in and in Biol. Chem. Full Text PDF PubMed Google Scholar). that ATX can on HDL and substrates to LPA D. to autotaxin and as a to LPA receptor in Sci. PubMed Scopus Google Scholar, R. A. A. C. S. et from and cells promotes and of the PubMed Scopus Google Scholar, M. A. C. A. R. S. J. et associated molecules are in plasma and in Sci. 2017; PubMed Scopus (52) Google Scholar). present that in the of genetically a high-fat Western increases the of LPA in HDL levels of LPA HDL and serum the effects of on LPA is LPA been to a in associated with R. A. A. C. S. et from and cells promotes and of the PubMed Scopus Google Scholar, M. A. C. A. R. S. J. et associated molecules are in plasma and in Sci. 2017; PubMed Scopus (52) Google Scholar). have that LPA with and that the effects of as increased to endothelial cells and LPA signaling (9Siess W. Zangl K.J. Essler M. Bauer M. Brandl R. Corrinth C. Bittman R. Tigyi G. Aepfelbacher M. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions.Proc. Natl. Acad. Sci. USA. 1999; 96: 6931-6936Crossref PubMed Scopus (369) Google Scholar, 10Zhou Z. Subramanian P. Sevilmis G. Globke B. Soehnlein O. Karshovska E. Megens R. Heyll K. Chun J. Saulnier-Blache J.S. et al.Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium.Cell Metab. 2011; 13: Full Text Full Text PDF PubMed Scopus Google Scholar). the genetically LDL-associated LPA for as as of the observed in plasma LPA by a high-fat Western that these LDL-associated LPA be that LDL-associated lysophospholipids can as substrates for of the associated with LDL, this is increased by which of LDL-associated can be to B. S. K. D. et of low density lipoprotein in normal and of lysophosphatidylcholine on Full Text PDF PubMed Google Scholar). might therefore in increased generation of LDL-associated LPA of this in to LDL or levels of LPA signaling the of LDL-associated LPA in many of the mechanisms to LDL We that serum LPA can to LDL, a that was to for the ATX-dependent increases in LDL-associated LPA observed in incubated plasma. LDL in humans is to have a of on of turnover of LDL-associated and may be is turnover of abundant LDL-associated T. density lipoprotein metabolism and lipoprotein in Full Text PDF PubMed Google Scholar). is to the importance of of LPA serum albumin and that ATX can on lipid substrates and that and that LDL are associated with significant increases in LDL-associated LPA pools in mice. LPA is associated with LDL isolated from human These have for efforts to associations circulating LPA levels and human disease risk that and levels of circulating particularly LDL, are of plasma LPA the as been for bioactive lipid association with S. E. C. M. R.L. Hla T. and PubMed Scopus Google might the signaling actions of LPA to cell signaling that be of LPA signaling in cardiovascular disease processes be to these autotaxin LDL receptor lysophosphatidic acid lysophosphatidylcholine proprotein convertase subtilisin/kexin type