title: Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis.
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.
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Mohamad
authors: M
authors: Navab
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Arnab
authors: A
authors: Chattopadhyay
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Greg
authors: G
authors: Hough
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: David
authors: D
authors: Meriwether
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Spencer I
authors: SI
authors: Fogelman
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Alan C
authors: AC
authors: Wagner
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Victor
authors: V
authors: Grijalva
authors: Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Feng
authors: F
authors: Su
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
authors: G M
authors: GM
authors: Anantharamaiah
authors: Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Lin H
authors: LH
authors: Hwang
authors: Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Kym F
authors: KF
authors: Faull
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736 Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Srinivasa T
authors: ST
authors: Reddy
authors: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
authors: Alan M
authors: AM
authors: Fogelman
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D050197:Atherosclerosis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D001583:Benzoxazoles / Q000494:pharmacology; D004041:Dietary Fats / Q000009:adverse effects; D050171:Dyslipidemias / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D054500:Group IB Phospholipases A2 / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency; D000099189:Lysophospholipase D
chemical_list: D001583:Benzoxazoles; D004041:Dietary Fats; D054500:Group IB Phospholipases A2; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D010879:Piperazines; D011973:Receptors, LDL; D000099189:Lysophospholipase D; C550725:6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one; C516203:Pla2g1b protein, mouse; C032881:lysophosphatidic acid
keywords: 6F peptide; apolipoprotein A-I mimetic peptides; genetically engineered tomato plants; lysophosphatidylcholine
references: Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1426-32
references: 15845909
references: Diabetes. 2006 Apr;55(4):935-41
references: 16567514
references: Annu Rev Cell Dev Biol. 2006;22:487-508
references: 16822172
references: J Lipid Res. 2007 Nov;48(11):2344-53
references: 17693626
references: Atherosclerosis. 2014 Jun;234(2):377-80
references: 24747111
references: Biochim Biophys Acta. 2000 Jan 3;1483(1):185-97
references: 10601707
references: Nat Cell Biol. 2000 Jun;2(6):326-32
references: 10854322
references: Biochem Biophys Res Commun. 1996 Jan 26;218(3):714-9
references: 8579579
references: J Biol Chem. 2008 Mar 21;283(12):7776-89
references: 18175805
references: Cell Metab. 2008 May;7(5):445-55
references: 18460335
references: J Lipid Res. 2008 Jun;49(6):1344-52
references: 18323573
references: Biochim Biophys Acta. 2008 Sep;1781(9):513-8
references: 18621144
references: J Lipid Res. 2009 Apr;50 Suppl:S225-30
references: 19066402
references: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):164-8
references: 19608977
references: Prostaglandins Other Lipid Mediat. 2010 Apr;91(3-4):130-8
references: 20331961
references: Am J Pathol. 2010 Jun;176(6):3073-84
references: 20431029
references: J Pharmacol Exp Ther. 2010 Jul;334(1):310-7
references: 20392816
references: FASEB J. 2010 Jul;24(7):2516-24
references: 20215528
references: J Lipid Res. 2011 Feb;52(2):361-73
references: 21068008
references: Nat Genet. 2011 Apr;43(4):333-8
references: 21378990
references: Cell Metab. 2011 May 4;13(5):592-600
references: 21531341
references: J Lipid Res. 2011 Jun;52(6):1200-10
references: 21444758
references: J Lipid Res. 2011 Nov;52(11):2005-11
references: 21908646
references: J Lipid Res. 2012 Mar;53(3):437-45
references: 22167743
references: Atherosclerosis. 2012 May;222(1):154-7
references: 22398276
references: Atherosclerosis. 2012 May;222(1):74-83
references: 22424734
references: Curr Opin Lipidol. 2012 Jun;23(3):235-40
references: 22327613
references: Circ Res. 2012 Jun 8;110(12):1575-84
references: 22556338
references: Br J Pharmacol. 2012 Oct;167(3):465-82
references: 22568609
references: Chem Rev. 2012 Oct 10;112(10):5121-46
references: 22742522
references: Biochim Biophys Acta. 2013 Jan;1831(1):105-8
references: 22561288
references: Biochim Biophys Acta. 2013 Jan;1831(1):99-104
references: 22710393
references: Biochim Biophys Acta. 2013 Jan;1831(1):126-32
references: 22835522
references: Biochim Biophys Acta. 2013 Jan;1831(1):42-60
references: 22867755
references: Biochim Biophys Acta. 2013 Jan;1831(1):20-32
references: 22884303
references: Biochim Biophys Acta. 2013 Jan;1831(1):109-16
references: 22892679
references: Biochim Biophys Acta. 2013 Jan;1831(1):33-41
references: 22902318
references: Biochim Biophys Acta. 2013 Jan;1831(1):61-73
references: 22960381
references: Biochim Biophys Acta. 2013 Jan;1831(1):213-22
references: 22986288
references: Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):52-9
references: 23104851
references: J Exp Med. 2012 Dec 17;209(13):2339-50
references: 23209312
references: J Lipid Res. 2013 Apr;54(4):995-1010
references: 23378594
references: J Lipid Res. 2013 May;54(5):1265-74
references: 23396975
references: Atherosclerosis. 2013 Jul;229(1):192-7
references: 23664202
references: J Lipid Res. 2013 Oct;54(10):2775-84
references: 23948545
references: Cell Metab. 2013 Nov 5;18(5):685-97
references: 24206663
references: J Lipid Res. 2013 Dec;54(12):3403-18
references: 24085744
references: J Lipid Res. 2013 Dec;54(12):3223-6
references: 24146211
references: Biochim Biophys Acta. 2014 Jan;1841(1):162-7
references: 24466591
references: J Lipid Res. 2014 Oct;55(10):2053-63
references: 24975585
references: J Lipid Res. 2014 Oct;55(10):1983-5
references: 25085258
references: J Clin Invest. 2001 Mar;107(5):585-93
references: 11238559
references: J Biol Chem. 2001 Jul 20;276(29):26745-52
references: 11352914
references: Biotechnol Bioeng. 2002 May 20;78(4):403-11
references: 11948447
references: Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E994-E1001
references: 12376327
references: J Biol Chem. 2002 Oct 18;277(42):39436-42
references: 12176993
references: Nat Rev Cancer. 2003 Aug;3(8):582-91
references: 12894246
references: Circulation. 2003 Oct 7;108(14):1735-9
references: 14504179
references: J Lipid Res. 2004 Jun;45(6):993-1007
references: 15060092
references: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11779-84
references: 15280540
references: J Biol Chem. 1988 Nov 25;263(33):17490-8
references: 3182858
references: J Lipid Res. 1995 Sep;36(9):2005-16
references: 8558088
references: Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):479-86
references: 24482375
references: Molecules. 2010 Mar;15(3):1354-77
references: 20335986
references: Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):837-45
references: 24504738
references: J Biochem. 1997 Jul;122(1):1-16
references: 9276665
references: Arch Biochem Biophys. 1998 Feb 15;350(2):201-13
references: 9473293
references: Biochemistry. 1999 Jun 15;38(24):7803-10
references: 10387020