2. Academic Validation
  3. Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

  • J Lipid Res. 2015 Apr;56(4):871-87. doi: 10.1194/jlr.M056614.
Mohamad Navab 1,  Arnab Chattopadhyay 1,  Greg Hough 1,  David Meriwether 2,  Spencer I Fogelman 1,  Alan C Wagner 1,  Victor Grijalva 1,  Feng Su 3,  G M Anantharamaiah 4,  Lin H Hwang 5,  Kym F Faull 5,  Srinivasa T Reddy 6,  Alan M Fogelman 1
Affiliations

Affiliations

  • 1 Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
  • 2 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.
  • 3 Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
  • 4 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
  • 5 Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-1736.
  • 6 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.
PMID: 25646365 DOI: 10.1194/jlr.M056614
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.

Keywords

6F peptide; apolipoprotein A-I mimetic peptides; genetically engineered tomato plants; lysophosphatidylcholine.

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