L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP. (January 2016)

• Record Type: Journal Article
• Authors: Collins, Heidi L.; Drazul-Schrader, Denise; Sulpizio, Anthony C.; Koster, Paul D.; Williamson, Yuping; Adelman, Steven J.; Owen, Kevin; Sanli, Toran; Bellamine, Aouatef
• Is Part Of: Atherosclerosis. Volume 244(2016)
• Page Start: 29
• Page End: 37
• Publication Date: 2016-01
• Subjects: Atherosclerosis -- l-carnitine -- TMAO -- Gut microbiota -- Cardiovascular disease; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.10.108
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Objective: Dietaryl -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 fedl -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 ofl -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. Conclusion: These findings suggest that TMAO slows aortic lesion formation in this mouse model and may have a protective effect against atherosclerosis development in humans. Highlights: An association between high levels of TMAO, a gut microbial degradation product ofl -Carnitine, and increased risk of atherosclerosis has been reported. TMAO was suggested to cause atherosclerosis by 1- promoting foam cell formation and 2- affecting reverse cholesterol transport (RCT). We performed experiments looking at the direct effect of TMAO on macrophage foam cell formation and on lesion progression in ApoE −/− mice expressing Human CETP. TMAO at levels higher than in humans did not affect foam cell formation in mouse macrophages. In mice, TMAO inversely correlated with decreased aortic lesion, suggesting a protective effect against lesion development. The doses ofl -carnitine used in the mouse experiment, corresponding to dietaryl -carnitine supplementation in Human, and leading to increased TMAO may provide protection against atherosclerosis development.