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• W2121323318 abstract "We previously reported that i) a Western diet increased levels of unsaturated lysophosphatidic acid (LPA) in small intestine and plasma of LDL receptor null (LDLR−/−) mice, and ii) supplementing standard mouse chow with unsaturated (but not saturated) LPA produced dyslipidemia and inflammation. Here we report that supplementing chow with unsaturated (but not saturated) LPA resulted in aortic atherosclerosis, which was ameliorated by adding transgenic 6F tomatoes. Supplementing chow with lysophosphatidylcholine (LysoPC) 18:1 (but not LysoPC 18:0) resulted in dyslipidemia similar to that seen on adding LPA 18:1 to chow. PF8380 (a specific inhibitor of autotaxin) significantly ameliorated the LysoPC 18:1-induced dyslipidemia. Supplementing chow with LysoPC 18:1 dramatically increased the levels of unsaturated LPA species in small intestine, liver, and plasma, and the increase was significantly ameliorated by PF8380 indicating that the conversion of LysoPC 18:1 to LPA 18:1 was autotaxin dependent. Adding LysoPC 18:0 to chow increased levels of LPA 18:0 in small intestine, liver, and plasma but was not altered by PF8380 indicating that conversion of LysoPC 18:0 to LPA 18:0 was autotaxin independent. We conclude that i) intestinally derived unsaturated (but not saturated) LPA can cause atherosclerosis in LDLR−/− mice, and ii) autotaxin mediates the conversion of unsaturated (but not saturated) LysoPC to LPA. We previously reported that i) a Western diet increased levels of unsaturated lysophosphatidic acid (LPA) in small intestine and plasma of LDL receptor null (LDLR−/−) mice, and ii) supplementing standard mouse chow with unsaturated (but not saturated) LPA produced dyslipidemia and inflammation. Here we report that supplementing chow with unsaturated (but not saturated) LPA resulted in aortic atherosclerosis, which was ameliorated by adding transgenic 6F tomatoes. Supplementing chow with lysophosphatidylcholine (LysoPC) 18:1 (but not LysoPC 18:0) resulted in dyslipidemia similar to that seen on adding LPA 18:1 to chow. PF8380 (a specific inhibitor of autotaxin) significantly ameliorated the LysoPC 18:1-induced dyslipidemia. Supplementing chow with LysoPC 18:1 dramatically increased the levels of unsaturated LPA species in small intestine, liver, and plasma, and the increase was significantly ameliorated by PF8380 indicating that the conversion of LysoPC 18:1 to LPA 18:1 was autotaxin dependent. Adding LysoPC 18:0 to chow increased levels of LPA 18:0 in small intestine, liver, and plasma but was not altered by PF8380 indicating that conversion of LysoPC 18:0 to LPA 18:0 was autotaxin independent. We conclude that i) intestinally derived unsaturated (but not saturated) LPA can cause atherosclerosis in LDLR−/− mice, and ii) autotaxin mediates the conversion of unsaturated (but not saturated) LysoPC to LPA. Our laboratories have been studying apoA-I mimetic peptides containing 18 amino acids for more than a decade (1Reddy S.T. Navab M. Anantharamaiah G.M. Fogelman A.M. Searching for a successful HDL-based treatment strategy.Biochim. Biophys. Acta. 2014; 1841: 162-167Crossref PubMed Scopus (22) Google Scholar). As a result of the success of the 4F peptide (peptide Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2) in multiple animal models of disease (2Navab M. Shechter I. Anantharamaiah G.M. Reddy S.T. Van Lenten B.J. Fogelman A.M. Structure and function of HDL mimetics.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 164-168Crossref PubMed Scopus (94) Google Scholar), clinical trials were undertaken with the 4F peptide that resulted in three reports (3Bloedon L.T. Dunbar R. Duffy D. Pinell-Salles P. Norris R. DeGroot B.J. Movva R. Navab M. Fogelman A.M. Rader D.J. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients.J. Lipid Res. 2008; 49: 1344-1352Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 4Dunbar R.L. Bloedon L.T. Duffy D. Norris R.B. Movva R. Navab M. Fogelman A.M. Rader D.J. Daily oral administration of the apolipoprotein A-I mimetic peptide D-4F in patients with coronary heart disease or equivalent risk improves high-density lipoprotein anti-inflammatory function (Abstract).J. Am. Coll. Cardiol. 2007; 49Google Scholar, 5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Two of these reports demonstrated efficacy, as measured by improvement in HDL anti-inflammatory properties, when the peptide was administered orally at high doses, despite achieving very low plasma peptide levels (3Bloedon L.T. Dunbar R. Duffy D. Pinell-Salles P. Norris R. DeGroot B.J. Movva R. Navab M. Fogelman A.M. Rader D.J. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients.J. Lipid Res. 2008; 49: 1344-1352Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 4Dunbar R.L. Bloedon L.T. Duffy D. Norris R.B. Movva R. Navab M. Fogelman A.M. Rader D.J. Daily oral administration of the apolipoprotein A-I mimetic peptide D-4F in patients with coronary heart disease or equivalent risk improves high-density lipoprotein anti-inflammatory function (Abstract).J. Am. Coll. Cardiol. 2007; 49Google Scholar). A third report described clinical trials in which low doses of peptide were administered intravenously or subcutaneously in order to achieve high plasma peptide levels with these low doses (5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Despite achieving high plasma peptide levels with these low doses, the third report was negative in terms of efficacy, as measured by the lack of improvement in HDL anti-inflammatory properties. The low doses used in the third report (5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar) had been tested in the first clinical trial, but these low doses were found not to be effective (3Bloedon L.T. Dunbar R. Duffy D. Pinell-Salles P. Norris R. DeGroot B.J. Movva R. Navab M. Fogelman A.M. Rader D.J. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients.J. Lipid Res. 2008; 49: 1344-1352Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). To understand the differing clinical trial results, we returned to mouse studies. In the first of these mouse studies, the amount of peptide in the feces predicted efficacy as measured by improvement in HDL anti-inflammatory properties and by decreases in plasma serum amyloid A (SAA) levels, but the plasma peptide levels did not predict efficacy (6Navab M. Reddy S.T. Anantharamaiah G.M. Imaizumi S. Hough G. Hama S. Fogelman A.M. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally.J. Lipid Res. 2011; 52: 1200-1210Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). In the next study, the peptide concentration in the small intestine of LDL receptor null (LDLR−/−) mice on a Western diet (WD) predicted efficacy as measured by the ability of the peptide to reduce tissue and plasma levels of proinflammatory oxidized metabolites of arachidonic and linoleic acids and by plasma SAA levels, but the plasma peptide levels again did not predict efficacy (7Navab M. Reddy S.T. Anantharamaiah G.M. Hough G. Buga G.M. Danciger J. Fogelman A.M. D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice.J. Lipid Res. 2012; 53: 437-445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In these mouse studies (6Navab M. Reddy S.T. Anantharamaiah G.M. Imaizumi S. Hough G. Hama S. Fogelman A.M. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally.J. Lipid Res. 2011; 52: 1200-1210Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 7Navab M. Reddy S.T. Anantharamaiah G.M. Hough G. Buga G.M. Danciger J. Fogelman A.M. D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice.J. Lipid Res. 2012; 53: 437-445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar), the dose required for efficacy was far above the highest dose tested in the human clinical trials that did not demonstrate efficacy (5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Additionally, we noted that the effective dose of these peptides tested in rabbits as measured by improvement in HDL anti-inflammatory properties, plasma SAA levels, and aortic atherosclerosis was also higher than the doses used in the third study (8Van Lenten B.J. Wagner A.C. Navab M. Anantharamaiah G.M. Hama S. Reddy S.T. Fogelman A.M. Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits.J. Lipid Res. 2007; 48: 2344-2353Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). These studies demonstrated a significant correlation between the anti-inflammatory properties of HDL and plasma SAA levels (P < 0.0001), a significant correlation between the anti-inflammatory properties of HDL and aortic atherosclerosis (P = 0.002), and a significant correlation between plasma SAA levels and aortic atherosclerosis (P = 0.0079) (8Van Lenten B.J. Wagner A.C. Navab M. Anantharamaiah G.M. Hama S. Reddy S.T. Fogelman A.M. Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits.J. Lipid Res. 2007; 48: 2344-2353Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). In normolipidemic monkeys, the dose required for efficacy as measured by improvement in HDL anti-inflammatory properties was also higher than the doses used in the third report (9Navab M. Anantharamaiah G.M. Reddy S.T. Van Lenten B.J. Ansell B.J. Fonarow G.C. Vahabzadeh K. Hama S. Hough G. Kamranpour N. et al.The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL.J. Lipid Res. 2004; 45: 993-1007Abstract Full Text Full Text PDF PubMed Scopus (570) Google Scholar, 10Navab M. Anantharamaiah G.M. Hama S. Hough G. Reddy S.T. Frank J.S. Garber D.W. Handattu S. Fogelman A.M. D-4F and statins synergize to render HDL anti-inflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1426-1432Crossref PubMed Scopus (143) Google Scholar). There were two reasons that a low dose of peptide was chosen for the clinical trials described in the third report, which did not demonstrate efficacy (5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). First, because of the need to chemically synthesize the 4F peptides, the cost of production was very high. Second, there was a mistaken belief that the peptides act primarily in the plasma, and that the level of peptide in plasma was the critical success factor. Our studies subsequent to the third report (5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar) suggested that high doses of peptide (40–100 mg/kg/day) must be delivered to the small intestine in order to achieve efficacy (6Navab M. Reddy S.T. Anantharamaiah G.M. Imaizumi S. Hough G. Hama S. Fogelman A.M. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally.J. Lipid Res. 2011; 52: 1200-1210Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 7Navab M. Reddy S.T. Anantharamaiah G.M. Hough G. Buga G.M. Danciger J. Fogelman A.M. D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice.J. Lipid Res. 2012; 53: 437-445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). The peptides used in the three reports of human clinical trials (3Bloedon L.T. Dunbar R. Duffy D. Pinell-Salles P. Norris R. DeGroot B.J. Movva R. Navab M. Fogelman A.M. Rader D.J. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients.J. Lipid Res. 2008; 49: 1344-1352Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 4Dunbar R.L. Bloedon L.T. Duffy D. Norris R.B. Movva R. Navab M. Fogelman A.M. Rader D.J. Daily oral administration of the apolipoprotein A-I mimetic peptide D-4F in patients with coronary heart disease or equivalent risk improves high-density lipoprotein anti-inflammatory function (Abstract).J. Am. Coll. Cardiol. 2007; 49Google Scholar, 5Watson C.E. Weissbach N. Kjems L. Ayalasomayajula S. Zhang Y. Chang I. Navab M. Hama S. Hough G. Reddy S.T. et al.Treatment of patients with cardiovascular disease with L-4F, an apoA-1 mimetic, did not improve select biomarkers of HDL function.J. Lipid Res. 2011; 52: 361-373Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar) contained blocked end groups, which can only be added by chemical synthesis. The cost of producing such chemically synthesized peptides for use at these high doses is prohibitive. Therefore, we searched for and found a peptide [peptide D-W-L-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F without blocked end groups (6F peptide)] that showed efficacy in mice as measured by plasma SAA levels and aortic atherosclerosis similar to the 4F peptides with blocked end groups (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. Lipid Res. 54: 3220.]): 995-1010Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Peptides that require blocked end groups for efficacy cannot be expressed as a transgene. Because the 6F peptide did not require blocked end groups for efficacy, we expressed 6F peptide in transgenic tomatoes (Tg6F tomatoes). When freeze-dried and fed to LDLR−/− mice on WD at only 2.2% by weight of the diet, Tg6F was highly effective in ameliorating dyslipidemia and atherosclerosis (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. Lipid Res. 54: 3220.]): 995-1010Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Feeding control tomatoes that were either wild type or made transgenic with the same vector, but containing a sequence for the expression of a control marker protein (β-glucuronidase) instead of 6F peptide, was not effective (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. Lipid Res. 54: 3220.]): 995-1010Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). The amelioration of dyslipidemia by Tg6F differed from earlier studies with the 4F peptide. The 4F peptide did not improve dyslipidemia but did improve HDL anti-inflammatory properties, plasma SAA levels, and atherosclerosis in animal models (1Reddy S.T. Navab M. Anantharamaiah G.M. Fogelman A.M. Searching for a successful HDL-based treatment strategy.Biochim. Biophys. Acta. 2014; 1841: 162-167Crossref PubMed Scopus (22) Google Scholar). After feeding the mice Tg6F tomatoes, intact 6F peptide was found in the small intestine, but the levels of 6F peptide were below the level of detection in the plasma (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. Lipid Res. 54: 3220.]): 995-1010Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). In the course of investigating possible mechanisms of action, we found that Tg6F tomatoes (but not control tomatoes) significantly reduced lysophosphatidic acid (LPA) levels in the small intestine (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. Lipid Res. 54: 3220.]): 995-1010Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Remarkably, the tissue content of unsaturated LPA in the small intestine significantly correlated with the extent of aortic atherosclerosis (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. Lipid Res. 54: 3220.]): 995-1010Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). LPA is emerging as an important signaling molecule in diverse biological processes and disease states (11Chattopadhyay A. Navab M. Hough G. Gao F. Meriwether D. Grijalva V. Springstead J.R. Palgunachari M.N. Namiri-Kalantari R. Su F. et al.A novel approach to oral apoA-I mimetic therapy.J. Lipid Res. 2013; 54 ([Erratum. 2013. J. 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Two pathways for lysophosphatidic acid production.Biochim. Biophys. Acta. 2008; 1781: 513-518Crossref PubMed Scopus (347) Google Scholar). The first pathway is illustrated by the example of phosphatidylcholine being acted on by phospholipase A1 (PLA1) or phospholipase A2 (PLA2) removing the acyl group from the sn-1 or sn-2 positions, respectively. Subsequently, lysophospholipase D (autotaxin) converts lysophosphatidylcholine (LysoPC) to LPA by removing choline from the sn-3 position of the lysophosphatidylcholine. The second pathway is illustrated by the exa" @default.
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