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
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
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
- 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.