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: Mohamad Navab, Arnab Chattopadhyay, Greg Hough, David Meriwether, Spencer I Fogelman, Alan C Wagner, Victor Grijalva, Feng Su, G M Anantharamaiah, Lin H Hwang, Kym F Faull, Srinivasa T Reddy, Alan M Fogelman
• Journal: Journal of lipid research (J Lipid Res) Vol. 56 Issue 4 Pg. 871-87 (Apr 2015) ISSN: 1539-7262 [Electronic] United States
• PMID: 25646365 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• 6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one
• Benzoxazoles
• Dietary Fats
• Lysophosphatidylcholines
• Lysophospholipids
• Piperazines
• Receptors, LDL
• Group IB Phospholipases A2
• Pla2g1b protein, mouse
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase
• lysophosphatidic acid

Topics

• Animals
• Aorta (drug effects)
• Atherosclerosis (blood, chemically induced, metabolism)
• Benzoxazoles (pharmacology)
• Dietary Fats (adverse effects)
• Dyslipidemias (blood, chemically induced, metabolism)
• Female
• Group IB Phospholipases A2 (metabolism)
• Intestinal Absorption (drug effects)
• Intestinal Mucosa (metabolism)
• Intestines (drug effects)
• Jejunum (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Lysophosphatidylcholines (pharmacology)
• Lysophospholipids (chemistry, metabolism, pharmacology)
• Male
• Mice
• Phosphoric Diester Hydrolases (metabolism)
• Piperazines (pharmacology)
• Receptors, LDL (deficiency)