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

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

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.

Highlights

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 LPA produced dyslipidemia and inflammation
We found that feeding Western diet (WD) to LDL receptor null (LDLRϪ/Ϫ) mice increased the levels of unsaturated LPA in the small intestine compared with feeding the mice standard mouse chow even though WD contained less preformed LPA than did standard mouse chow [39]
The studies reported here demonstrate that adding unsaturated to standard mouse chow produces aortic atherosclerosis similar to that seen on feeding LDLRϪ/Ϫ mice WD

Summary

Introduction

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. The peptide concentration in the small intestine of LDL receptor null (LDLRϪ/Ϫ) 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 [7] In these mouse studies [6, 7], the dose required for efficacy was far above the highest dose tested in the human clinical trials that did not demonstrate efficacy [5]. 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 higher than the doses used in the third study [8]. The dose required for efficacy as measured by improvement in HDL antiinflammatory properties was higher than the doses used in the third report [9, 10]

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Results

Discussion

Conclusion