title: L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE(-/-) transgenic mice expressing CETP.
abstract: OBJECTIVE
  Dietary l-carnitine can be metabolized by intestinal microbiota to trimethylamine, which is absorbed by the gut and further oxidized to trimethylamine N-oxide (TMAO) in the liver. TMAO plasma levels have been associated with atherosclerosis development in ApoE(-/-) mice. To better understand the mechanisms behind this association, we conducted in vitro and in vivo studies looking at the effect of TMAO on different steps of atherosclerotic disease progression.
  
  
  METHODS
  J774 mouse macrophage cells were used to evaluate the effect of TMAO on foam cell formation. Male ApoE(-/-) mice transfected with human cholesteryl ester transfer protein (hCETP) were fed l-carnitine and/or methimazole, a flavin monooxygenase 3 (FMO3) inhibitor that prevents the formation of TMAO. Following 12 week treatment, l-carnitine and TMAO plasma levels, aortic lesion development, and lipid profiles were determined.
  
  
  RESULTS
  TMAO at concentrations up to 10-fold the Cmax reported in humans did not affect in vitro foam cell formation. In ApoE(-/-)mice expressing hCETP, high doses of l-carnitine resulted in a significant increase in plasma TMAO levels. Surprisingly, and independently from treatment group, TMAO levels inversely correlated with aortic lesion size in both aortic root and thoracic aorta. High TMAO levels were found to significantly correlate with smaller aortic lesion area. Plasma lipid and lipoprotein levels did not change with treatment nor with TMAO levels, suggesting that the observed effects on lesion area were independent from lipid changes.
  
  
  CONCLUSIONS
  These findings suggest that TMAO slows aortic lesion formation in this mouse model and may have a protective effect against atherosclerosis development in humans.
authors.affiliation: VascularStrategies LLC, United States.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Collins
authors.affiliation: VascularStrategies LLC, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Drazul-Schrader
authors.affiliation: VascularStrategies LLC, United States.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Sulpizio
authors.affiliation: VascularStrategies LLC, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Koster
authors.affiliation: Lonza Inc., United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Williamson
authors.affiliation: VascularStrategies LLC, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Adelman
authors.affiliation: Lonza Inc., United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Owen
authors.affiliation: KGK Synergize Inc., Canada.
authors.forename: Toran
authors.initials: T
authors.lastname: Sanli
authors.affiliation: Lonza Inc., United States. Electronic address: aouatef.bellamine@lonza.com.
authors.forename: Aouatef
authors.initials: A
authors.lastname: Bellamine
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood*; D002331:Carnitine / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000096:biosynthesis*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008744:Methylamines / Q000097:blood*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008744:Methylamines; C005855:trimethyloxamine; D002331:Carnitine
keywords: Atherosclerosis; Cardiovascular disease; Gut microbiota; TMAO; l-carnitine