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. ...

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