J. Lipid Res.-2019-Kraemer-jlr.M093096.pdf Maria Kraemer Guogen Mao Courtney Hammill baoxiang yan fredrick onono Yu Li Susan S. Smyth Andrew J. Morris 10.25376/hra.9999275.v1 https://hra.figshare.com/articles/journal_contribution/J_Lipid_Res_-2019-Kraemer-jlr_M093096_pdf/9999275 Lysophosphatidic acids (LPA) 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 low-density lipoproteins (LDL). The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined effects of experimental hyperlipidemia on 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 PCSK9 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. 2019-10-17 18:21:04 lysophosphatidic acid hyperlipidemia cholesterol lipoprotein LDL Autotaxin mass spectrometry Medical Biochemistry: Lipids