12 Nov Study Examines Link Between L-Carnitine and Atherosclerosis
MedicalResearch.com Interview with:
Medical Research: What is the background for this study? What are the main findings?
Dr. Bellamine: About two years ago, Robert Koeth and his colleagues (Nat Med. 2013 May;19(5):576-85) published a paper linking atherosclerosis and increased cardiac disease risks to Trimethylamine N-oxide (TMAO), a degradation product of dietary quaternary ammonium compounds such as L-Carnitine, Betaine and Choline. When these compounds are not completely absorbed into the intestine, bacterial gut metabolizes them to TMA (Trimethylamine) which is absorbed to the blood and further metabolized by the liver flavin-containing mono-oxygenases (FMOs) to TMAO. This is why some people use injectable l carnitine products.
Koeth’s observation was based on
- 1- clinical association between L-Carnitine levels increased incidence of major cardiac events,
- 2- on increased lesion formation in ApoE-/- mouse, a disease model used to study atherosclerosis.The conclusion was that TMAO promotes atherosclerosis. Although the association is established, the cause to effect cannot be clarified given the lack of dose response in this mouse model (a single dose has been used) and the small number of animals in the treatment group making the difference between treatments (3 out of 11 animals). In addition, TMAO has been described to play the role of a molecular chaperone, preventing the protein unfolding. TMAO is also found in fish where it plays an important role in maintaining a normal osmolality. Fish is reported otherwise to be a healthy food source and its consumption is not linked to atherosclerosis occurrence.
Lonza decided to investigate the mechanism (s) behind these observations (Bellamine et al., Experimental Biology meeting, San Diego, 28 April 2014, Bellamine et al., Atherosclerosis in press). First, we showed that increasing TMAO levels up to 10-fold the Cmax as reported in humans, did not affect the foam cell formation in vitro, an obligatory step in the atherosclerosis disease progression.
Second, we used an improved version of the ApoE-/- mouse model, expressing the cholesteryl ester transport protein (CETP) lacking normally in rodents. The CETP plays a major role in the cholesterol re-cycling in humans and its inhibition has been studied as a target for atherosclerosis treatment.
Further, we used different doses of dietary L-Carnitine, leading to different levels of TMAO in an attempt to establish a dose-response curve. We found that TMAO levels inversely correlated with the lesion size. Significantly reduced aortic lesion size was observed at high levels of TMAO. These effects were independent from lipid changes.
These observations suggest that TMAO may play a protective role in atherosclerosis disease development by reducing the lesion formation. When the lesions start developing, the TMAO levels would be up-regulated by a compensatory mechanism (possibly by increasing FMOs expression levels).
Medical Research: What should clinicians and patients take away from your report?
Dr. Bellamine: We believe that it is very important to keep in mind the crucial role that L-Carnitine plays in energy metabolism and muscle health. This is particularly true for people lacking the adequate levels of L-Carnitine (vegetarians, infants, elderly, hemodialysis patients). We showed that TMAO, a by-product of L-Carnitine and other similar molecules, is not harmful but rather benefits heart health, providing more assurance on its safety. Since our initial report (Bellamine et al., Experiment Biology meeting, San Diego, 28 April, 2014),several scientists started studying the potential beneficial effects of TMAO in atherosclerosis disease. Fukami et al., reported early this year that L-Carnitine consumption by hemodialysis patients, leading to increased TMAO blood levels, correlated with a decrease in the vascular injury markers (J Cardiovasc Pharmacol Volume 65, Number 3, March 2015). Monte and colleagues found no significant association between carotid intimal medial thickness and L-Carnitine or TMAO levels (Can J Cardiol. 2015 Jun 25. [Epub ahead of print]). In a third trial, Kaysen and colleagues reported that TMAO levels inversely correlated with markers of inflammation (hCRP) and did not correlated with all-cause mortality, cardiovascular death, or hospitalizations in hemodialysis patients (J Ren Nutr. 2015 Jul;25(4):351-6). Hence, we can conclude that TMAO is not harmful but rather may protect against atherosclerosis, and that L-Carnitine consumption leading to increased TMAO levels can only benefit those segments of the population who lack adequate levels of .
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Bellamine: We believe that more mechanistic studies which evaluate the regulation of certain genes (e. g. FMOs, reverse cholesterol pathway) will further clarify the mechanism (s) by which TMAO may overcome lesion development. Intervention studies in both animals and in the clinic should provide greater clarity on the molecular mechanism and how TMAO may play an important role in the atherosclerosis disease progression. This could be a potential new target for atherosclerosis treatment.
L-carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE-/- transgenic mice expressing CETP
Heidi L. Collins, D., Denise Drazul-Schrader, S., Anthony C. Sulpizio, S., Paul D. Koster, A., Yuping Williamson, S., Steven J. Adelman, D., Kevin Owen, D., Toran Sanli, D , Aouatef Bellamine, D.
Available online 2 November 2015
Study Examines Link Between L-Carnitine and Atherosclerosis (2015). Study Examines Link Between L-Carnitine and Atherosclerosis