Role of enterocyte Enpp2 and autotaxin in regulating lipopolysaccharide levels,systemic inflammation,and atherosclerosis |
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Affiliation: | 1. Division of Cardiology, Department of Medicine, Fielding School of Public Health, University of California, Los Angeles, CA, USA;2. The Vatche and Tamar Manoukian Division of Digestive Diseases, Fielding School of Public Health, University of California, Los Angeles, CA, USA;3. UCLA Microbiome Center, Fielding School of Public Health, University of California, Los Angeles, CA, USA;4. David Geffen School of Medicine at UCLA and the Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Administration Greater Los Angeles Healthcare System Los Angeles, Fielding School of Public Health, University of California, Los Angeles, CA, USA;5. Molecular Toxicology Interdepartmental Degree Program, Fielding School of Public Health, University of California, Los Angeles, CA, USA;6. Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands;7. Department of Molecular and Medical Pharmacology, Fielding School of Public Health, University of California, Los Angeles, CA, USA |
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Abstract: | Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr−/− mice standard mouse chow supplemented with unsaturated LPA or lysophosphatidylcholine qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet (WD). Here, we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species and oxidized phospholipids (OxPLs) in jejunum mucus. To determine the role of intestinal autotaxin, enterocyte-specific Ldlr−/−/Enpp2 KO (intestinal KO) mice were generated. In control mice, the WD increased enterocyte Enpp2 expression and raised autotaxin levels. Ex vivo, addition of OxPL to jejunum from Ldlr−/− mice on a chow diet induced expression of Enpp2. In control mice, the WD raised OxPL levels in jejunum mucus and decreased gene expression in enterocytes for a number of peptides and proteins that affect antimicrobial activity. On the WD, the control mice developed elevated levels of lipopolysaccharide in jejunum mucus and plasma, with increased dyslipidemia and increased atherosclerosis. All these changes were reduced in the intestinal KO mice. We conclude that the WD increases the formation of intestinal OxPL, which i) induce enterocyte Enpp2 and autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of reactive oxygen species that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma lipopolysaccharide levels that promote systemic inflammation and enhance atherosclerosis. |
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Keywords: | lysophospholipase D lysophosphatidic acid atherosclerosis oxidized phospholipids small intestine apolipoprotein A-I mimetic peptides transgenic tomatoes expressing the apoA-I mimetic peptide 6F cDNA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" complementary DNA CXCL1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" C-X-C motif chemokine ligand 1 FACS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" fluorescence-activated cell sorting iKO" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" intestinal KO LPA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" lysophosphatidic acid LPC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" lysophosphatidylcholine Lpcat3" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" LPC acyltransferase 3 LPS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" lipopolysaccharide OxPL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" oxidized phospholipid PLPP3" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" phospholipid phosphatase 3 qPCR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" quantitative PCR ROS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" reactive oxygen species SAA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" serum amyloid A TgF6" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" transgenic tomatoes expressing the apoA-I mimetic peptide 6F VilCre" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" Villin Cre WD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0200" }," $$" :[{" #name" :" text" ," _" :" Western diet |
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