The nutrients L-carnitine and choline are two of the most important for heart and liver health. Large bodies of literature support the benefits of these compounds and that of related items, such as phosphatidylcholine. Despite this history, recently news media articles have appeared suggesting that these nutrients actually cause heart disease. Similarly, in the medical professional research literature, there is a groundswell of publications that attempt to associate L-carnitine and choline with cardiovascular disease through entirely indirect arguments involving primarily the compound trimethylamine-N-oxide.
In a nutshell, these publications cast aside direct clinical evidence that supplementing with L-carnitine and choline improves heart and liver health by focusing, instead, on marker compounds in the blood and correlations between these and illness without establishing causation. The presence of a biochemical marker is used to overturn clinical evidence such that compounds proven in practice to be good for health suddenly are associated with disease. As argued in the following paragraphs, this guilt by association does not withstand close scrutiny.
L-Carnitine and Choline
Although the L-carnitine is usually referred to as an amino acid, this is technically incorrect inasmuch as there is no amino (NH2) group present in the molecule. The primary role of L-carnitine in the body is as a biocatalyst or coenzyme. One of the most important functions of L-carnitine is in the oxidation of long chain fatty acids, a process which takes place inside of mitochondria, the “energy factories” of the cells. This process is known as beta-oxidation. L-Carnitine acts as a shuttle for bringing fatty acids into the mitochondria and then removing waste afterwards. Fats are the preferred source of fuel for the kidneys, the skeletal muscles, and even more so for the heart muscle. As much as 70 percent of the energy generated in muscle tissue comes from the oxidation of fats!
L-Carnitine also increases the rate of oxidation of fats in the liver, and this suggests that it plays a role in energy generation from this angle as well.1 Some authors argue that in the proper amounts, L-carnitine supplementation during dieting can help to control the negative effects of ketosis (the accumulation of waste products of fat metabolism) in those who are susceptible to this problem.2 Similarly, there is evidence that some forms of obesity may be related to a genetic propensity to produce less L-carnitine, and liver and kidney problems will reduce the body’s production since some four fifth’s of our total L-carnitine is produced internally by these organs.3,4
L-Carnitine has been shown to have positive benefits upon the myocardium of the heart and upon peripheral circulation. The effects upon the heart include improvements in energy production and other parameters. Supplemental L-carnitine is associated with significantly higher concentrations of pyruvate, ATP and creatine phosphate in portions of the heart muscle during conditions of extreme stress.5 Similarly, in tests upon peripheral circulation, L-carnitine has been found to be quite useful for improving blood flow.6 Of course, the true test of the benefits of L-carnitine is survival: In a randomized controlled trial, there was a 90 percent decrease in mortality over the next 12 months compared with people who did not receive L-carnitine when patients started supplementing shortly after suffering a heart attack.7 Another study analyzing 13 controlled trials (involving a variety of settings) found that L-carnitine led to a 27 percent reduction in all-cause mortality.8 Choline, phosphatidylcholine and related compounds are especially protective of liver health, including in both nonalcoholic and alcoholic fatty liver disease.9,10 Liver dysfunction is extremely common in those who carry excessive weight and is viewed as causative in diabetes type 2. L-Carnitine and choline reduce overall oxidative stress in individuals and lower lipid peroxidation, recognized factors in promoting cardiovascular and liver health.11
L-Carnitine Slows Plaque Formation in Arteries Despite TMAO
A paper published in the journal Atherosclerosis (2016) reconfirms some of the health benefits of L-carnitine and, by implication, those of choline, phosphatidylcholine and related nutrients. In a nutshell, researchers fed supplemental L-carnitine to mice for 12 weeks and then observed aortic lesion development and blood lipid profiles. These scientists wanted to test the truth of a vast body of older science that demonstrated the cardioprotective properties of L-carnitine versus new theories that gut microbes transform L-carnitine into trimethylamine (TMA) that the liver further transforms into trimethylamine-N-oxide (TMAO) that promotes atherosclerosis. The researchers found that L-carnitine supplementation slows aortic lesion formation in their mouse model. L-Carnitine was heart protective just as indicated in previous research based on examining clinical results rather than looking only at short term markers purported to indicate future results (endpoints versus markers). Moreover, TMAO, the supposedly toxic metabolite of L-carnitine, actually appeared to protect the arteries. One implication of this study is that L-carnitine, including its metabolite TMAO, may be similarly protective against atherosclerosis development in humans.
The current study was designed to test the hypothesis of an article published in Nature Medicine (2013) that suggested that the nutrient L-carnitine, found in red meat and nutritional supplements, promotes atherosclerosis as a result of bacteria in the gut forming a toxin called trimethylamine (TMA), which is further metabolized in the liver to trimethylamine-Noxide (TMAO).13 Two follow-up articles by many of the same Nature Medicine authors argue that gut bacteria similarly transform dietary betaine, choline and phosphatidylcholine (and presumably other choline-related nutrients) to yield TMA followed by TMAO with negative cardiovascular consequences. Since the initial publications, there has been a flood of research putatively supporting the original findings. Inasmuch as TMAO plasma levels have been associated with atherosclerosis development in the particular mouse model used in the initial research, the goal was to better understand the mechanisms behind the TMAO/CVD association. The Atherosclerosis (2016) research was designed to investigate both in vitro (isolated cell or tissue) mechanisms—does TMAO promote foam cells formation—and in vivo (live animal) endpoints—does TMAO promote or inhibit lesion development in the arteries.
The in vitro part of the study demonstrated that TMAO at concentrations up to ten times the maximum reported in humans did not affect foam cell formation. In other words, there was no indication that a mechanism exists through which TMAO causes damage to the lining of the arteries. However, there still were outstanding issues, such as why TMAO was both elevated in the usual mouse model and linked to increased levels of atherosclerosis.
The in vivo part of the study provides important answers to these issues. First, it must be understood that rodents in general process lipids, including cholesterol, differently than do humans. For instance, the usual mouse model for atherosclerosis lacks cholesteryl ester transfer protein (hCETP), which in humans is involved in the movement of cholesterol between high density lipoprotein (HDL) and low density lipoprotein cholesterol (LDL). Using a model that more properly matches human lipid metabolism, high doses of L-carnitine resulted in a significant increase in plasma TMAO levels, yet—and regardless of treatment—TMAO levels were inversely correlated with aortic lesion size. Indeed, as the blood levels of TMAO went up, the size of the aortic lesion area went down and this bore no relation to changes in blood lipids. One clear implication of these findings is just the opposite of that commonly being suggested regarding TMAO, to wit, TMAO is protective of arterial health rather than being a toxin.
So What Goes Wrong in Humans to Elevate TMAO?
There is little doubt that ingestion of L-carnitine, betaine, choline and related nutrients can increase TMAO levels in many individuals and that increased TMAO also can be associated in many cases with increased cardiovascular disease. However, it is becoming increasingly clear that TMAO is not a cause of atherosclerosis.
Study after study after study that has looked at clinical endpoints, meaning the actual outcomes of the use of L-carnitine with human beings, has shown significant benefits across a wide array of heart and circulatory issues.14 Benefits are found with choline, phosphatidylcholine and related nutrients along with eating oily fish, a practice that necessarily dramatically increases TMAO, yet supports good health.
This is a classic case of blaming a messenger for the message. Just as with TMAO, elevated blood levels of choline sometimes are seen in patients with artery plaque instability, but this is a result of the instability itself and is unrelated to supplements just as an analogously disturbed L-carnitine regulation arguably is a result of cardiovascular problems and not due to dietary intake.15,16 In a clinical trial, oral L-carnitine supplementation increased trimethylamine-N-oxide, but reduced indications of vascular injury in hemodialysis patients.17 Elevated TMAO blood levels are associated with low HDL and related disturbances just as elevated TMAO levels appear to be linked to impaired kidney function and poor metabolic control.18,19 The clear implication is that TMAO levels may reveal problems that originate elsewhere in the body and that artificially lowering TMAO blood levels will not improve health because TMAO is not the cause of these issues. The key concept here is to look at "endpoints," not "markers."
Meat, poultry, fish, and dairy products are the richest food sources of L-carnitine, although L-carnitine intake probably is increased best via supplements. This route is not so necessary for betaine, choline and a number of related nutrients. According to the Linus Pauling Institute, the consumption of choline is far below the recommended intake in the United States. Rich sources of choline include eggs, liver, wheat germ, many types of seafood and even peanuts. According to Whole Foods, vegetable options include collard greens, Brussels sprouts, broccoli, Swiss chard, cauliflower, and asparagus. A large listing of food sources can be found at http://nutritiondata.self.com/. Many choline sources also are good sources of phosphatidylcholine (liver, egg yolk, peanuts). Choline's metabolite betaine can be found in spinach, beets and shellfish.
- Preuss HG, Mrvichin N, Clouatre D, et al. Importance of Fasting Blood Glucose in Screening/Tracking Overall Health. The Original Internist. 2016, March:13¡V15,17¡V18.
- Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 1999 Jan;22(1):45¡V9.
- Sears B. Anti-inflammatory Diets. J Am Coll Nutr. 2015;34 Suppl 1:14¡V21.
- Mauro DiPasquale, M.D., "Let the Fat be with You: The Ultimate High-Fat Diet," Muscle Magazine International (July and September 1992); "High Fat, High Protein, Low Carbohydrate Diet: Part I," Drugs in Sports 1, 4 (December 1992) 8¡V9.
- Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 Dec;130(12):2990¡V5.
- Lim K, Ryu S, Suh H, Ishihara K, Fushiki T. (-)-Hydroxycitrate ingestion and endurance exercise performance. J Nutr Sci Vitaminol (Tokyo). 2005 Feb;51(1):1¡V7.
- Cheng IS, Huang SW, Lu HC, Wu CL, Chu YC, Lee SD, Huang CY, Kuo CH. Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle. Br J Nutr. 2012 Apr;107(7):1048¡V55.
- Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (¡V)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2(1):23. See also notes 18 and 19.
- Clouatre D, Talpur N, Talpur F, Echard B, Preuss H. Comparing metabolic and inflammatory parameters among rats consuming different forms of hydroxycitrate. Journal of the American College of Nutrition 2005;24:429 Abstract.
- Clouatre D, Preuss HG. Potassium Magnesium Hydroxycitrate at Physiologic Levels Influences Various Metabolic Parameters and Inflammation in Rats. Current Topics in Nutraceutical Research 2008;6(4): 201¡V10.
- Han N, Li L, Peng M, Ma H. (-)-Hydroxycitric Acid Nourishes Protein Synthesis via Altering Metabolic Directions of Amino Acids in Male Rats. Phytother Res. 2016 May 4. doi: 10.1002/ptr.5630. [Epub ahead of print]
- Lim JS, Adachi Y, Takahashi Y, Ide T. Comparative analysis of sesame lignans (sesamin and sesamolin) in affecting hepatic fatty acid metabolism in rats. Br J Nutr. 2007 Jan;97(1):85¡V95.
- Ide T, Lim JS, Odbayar TO, Nakashima Y. Comparative study of sesame lignans (sesamin, episesamin and sesamolin) affecting gene expression profile and fatty acid oxidation in rat liver. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):31¡V43.
- Henry-Vitrac C, Ibarra A, Roller M, Merillon JM, Vitrac X. Contribution of chlorogenic acids to the inhibition of human hepatic glucose-6-phosphatase activity in vitro by Svetol, a standardized decaffeinated green coffee extract. J Agric Food Chem. 2010 Apr 14;58(7):4141¡V4.
- Bassoli BK, Cassolla P, Borba-Murad GR, et al. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. 2008 Apr;26(3):320 ¡V8.
- Malmsten C, Lignell A. Dietary Supplementation with Astaxanthin- Rich Algal Meal Improves Strength Endurance; A Double Blind Placebo Controlled Study on Male Students. Carotenoid Science. 2008;13:20 ¡V22.
- Aoi W, Naito Y, Takanami Y, Ishii T, Kawai Y, Akagiri S, Kato Y, Osawa T, Yoshikawa T. Astaxanthin improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification. Biochem Biophys Res Commun. 2008 Feb 22;366(4):892¡V7.