L-carnitine: a slim figure and atherosclerosis in the load?

Don't trust the ads, or the potential connection
metabolism of L-carnitine and the development of atherosclerosis

Evgenia Prokhorova, "Biomolecule"

Heavy consumption of meat products in developed countries is associated with an increased risk of cardiovascular diseases, explaining this by the high content of saturated fats and cholesterol in meat. But is it so? Studies in 2013 did not confirm the connection between the consumption of saturated fats and an increased risk of developing cardiovascular diseases [1], which prompted scientists to search for other factors leading to pathology. That's when they remembered about another feature of meat products - the abundant content of L-carnitine.

Increased consumption of L-carnitine is gaining popularity due to its beneficial effect on the human condition. However, the absence of side effects of excessive consumption of L-carnitine has not been proven.

Think about what you are buying!L-carnitine was first isolated by two Russian scientists in 1905.

Consequently, it is now the second century since the discovery and the beginning of the study of the role of this molecule in the human body [2]. This is one of the most researched components of food. Food, namely red meat, is the main source of carnitine in omnivorous animals; however, a little L–carnitine is synthesized from lysine in the body itself.

In addition, more and more people are consuming L-carnitine as a dietary supplement. In addition to online stores, sports nutrition stores and pharmacies, carnitine began to be found even on the shelves of grocery stores in our country, including as part of vitamins, energy drinks, chocolate bars and other things. Anyone can buy L-carnitine or products containing it. In most cases, L-carnitine is taken, apparently, in the hope of intensifying the destruction of fats, since it is believed that it transports fatty acids into the mitochondrial matrix, where their destruction occurs with the release of energy (Fig. 1).

Figure 1. Participation of L-carnitine in the transport of fatty acids from the cytoplasm to the mitochondria for beta-oxidation and energy production. CPT – carnitine palmitoyltransferase, CT – carnitine acylcarnitine translocase, CoA – coenzyme A.Advertising of L-carnitine promises rapid weight loss, increased muscle mass, improved mental and physical fitness, resistance to stress, detoxification of the body and much more.

I must say that many of the positive effects of carnitine are really scientifically proven, but do not forget that it is still unknown whether excess carnitine is harmful to health.

The consumption rate of L-carnitine for an adult is 300 mg, whereas for weight loss and improving athletic performance, doses from 500 mg to 2 g per day are considered optimal. In the hope of finding the perfect body, while making a minimum of effort, people exceed the norm several times, without thinking about the possible consequences. But in vain. After all, we know that the metabolic pathways in the body are insufficiently studied, and that almost all medications – yes, even vitamins with their excessive use – have side effects. And L-carnitine is no exception! Studies in 2013 showed that the metabolite of L-carnitine, trimethylamine oxide (TMAO), is a substance that contributes to the development of atherosclerosis [3].

Insidious bacteria, or a new look at the metabolism of L-carnitineThe discovery of 2011, which showed the connection of choline metabolism - a structural analogue of L–carnitine - with the pathogenesis of cardiovascular diseases, made us think about the possible connection of L–carnitine with the development of atherosclerosis [3].

The main source of choline is phosphatidylcholine, one of the most common molecules of cell membranes, which is contained in large quantities in food of animal origin.

As it turned out, choline is used by some intestinal bacteria for the synthesis of trimethylamine intermediate (TMA) (Fig. 2). In turn, TMA is rapidly absorbed and oxidized by enzymes of the FMO family (flavin monooxygenase, FMO3 – the main enzyme of the process) in the liver to TMAO, causing the development of atherosclerosis.

Figure 2. Scheme of synthesis of phosphatidylcholine metabolite stimulating the development of atherosclerosis by intestinal flora [3]. Phosphatidylcholine serves as a source of choline, which some intestinal bacteria are able to use for the synthesis of TMA. TMA, in turn, is rapidly converted by the enzyme flavin monooxygenase into TMAO, the level of which showed a strict correlation with the development of atherosclerosis.The use of the trimethylamine group of choline by bacteria for the synthesis of TMA raises the question of the existence of similar metabolic pathways for similar compounds including this group.

One of these molecules is carnitine (Fig. 3). The assumption that TMAO production from L–carnitine is linked was confirmed by studies in 2013 [1], although previous experiments on rats did not reveal such a connection [4].

Figure 3. Scheme of TMAO synthesis leading to the development of atherosclerosis [1]. Carnitine and choline – trimethylamines obtained from food – are used for the synthesis of TMA by the intestinal microflora, which is rapidly oxidized by flavin monooxygenase to TMAO.The metabolite of L-carnitine is one of the causes of the development of cardiovascular diseases

Two independent clinical studies have shown an association between the concentration of L-carnitine and TMAO in blood plasma with the development of coronary and peripheral insufficiency, as well as cardiovascular diseases in general.

The first study involved a group of 2,595 people [1], the second one involved a three–year cardiological control of 4,000 patients [5].

Studies in mice also confirm the correlation of high levels of L-carnitine and TMAO with the development of pathologies of the cardiovascular system [1]. From the age of four weeks, four groups of mice received a certain type of nutrition: 1) regular, 2) with an increased carnitine content, 3) with the addition of antibiotics, or 4) with an increased carnitine content and the addition of antibiotics. Comparison of aortic root tissue in mice at the age of 19 weeks revealed a double increase in the area of atherosclerotic damage when L-carnitine was added to the feed (Fig. 4, 5A).

Figure 4. Sections of the aortic roots of 19-week-old mice [1]. Staining with hematoxylin. Chow – normal nutrition, ABS – absence of an antibiotic.In mice receiving L-carnitine in combination with antibiotics, there were no violations.

Consequently, the culprits of the development of cardiovascular disorders are bacteria involved in the formation of TMAO, the level of which increases significantly with the consumption of L–carnitine (Fig. 5B) and correlates with the development of atherosclerosis.

Figure 5. A. Assessment of the area of atherosclerotic damage to the aortic roots in mice depending on the type of nutrition. B. Dependence of the level of TMAO on the type of nutrition of mice [1]. Chow – normal nutrition, ABS – absence of an antibiotic.Let's remember about vegans (radical vegetarians who do not consume any animal products) and vegetarians who do not consume red meat with a high content of L-carnitine, and think about whether they have a group of bacteria in their intestines responsible for the formation of TMA, oxidizing to TMAO (Fig. 3)?

It is no secret that food preferences determine the composition of the microbiota [6]. Thus, a prolonged excess of carnitine in food leads to changes in the composition of the intestinal flora, contributing to the prosperity of bacteria involved in the synthesis of TMAO [1]. Reduced consumption of L-carnitine and choline in vegans and vegetarians, on the contrary, does not allow them to develop. There are practically no bacteria synthesizing TMAO, and even when L-carnitine is included in the diet of people who have been following a plant-based diet for a long time, the level of TMAO in blood plasma and urine remains low (Fig. 6).

Figure 6. Comparison of TMAO levels in blood plasma (A) and urine (B) after taking L-carnitine in vegans and people who consume red meat products almost daily [1]. The synthesis of TMAO (or its d3-labeled analog) after consumption of meat steak and L-carnitine (or d3-methyl carnitine) is insignificant in vegans (who have been refusing animal products for more than 5 years), unlike people who regularly consume red meat. The data obtained were further tested and confirmed on people following a regular diet and people leading a vegan or vegetarian lifestyle for more than a year.From this it can be assumed that the low level of TMAO is the main reason for the good state of the cardiovascular system of vegans and vegetarians.

After all, statistics show us a rarer occurrence of cardiovascular diseases [7, 8] and a 29% reduced risk of death from cardiac ischemia for people in this group [8].

Experiments also suggest that following a balanced plant-based diet leads to a decrease in blood pressure, cholesterol levels and the risk of atherosclerosis [8-10]. So, the refusal of animal food can reduce the intake of medications for cardiovascular disorders. In one study, a group of patients with atherosclerosis was offered a complete transition to plant foods. A year later, 82% of the group showed improvements [11]. Repetition of the experiment led to similar results [12].

But perhaps the benefits of following a plant-based diet are not at all due to the lack of TMAO synthesis, but to the low content of saturated fats and cholesterol in the diet? After all, there is a widespread opinion that it is the consumption of large amounts of saturated fats and cholesterol that is the main risk factor for the development of atherosclerosis. However, studies in 2013 did not confirm this connection [1]. It is also noteworthy that the development of atherosclerotic lesions in mice occurred in the absence of changes in the composition and content of lipids, lipoproteins, glucose and insulin levels. Moreover, no signs of obesity could be detected in such mice.

So it is possible that intestinal bacteria involved in the synthesis of TMAO are the main culprits of the development of atherosclerosis. If this is the case, then the use of antibiotics is a new possible way to combat cardiovascular diseases, as well as to prevent them. Genera of bacteria, presumably involved in the synthesis of TMAO, have already been identified for both humans and mice. And although the data obtained is not yet sufficient to identify a common taxon responsible for the synthesis of TMAO, further research will soon clarify the situation.

How dangerous is atherosclerosis and what is the role of TMAO in its development?Cardiovascular diseases annually claim the largest number of human lives among all diseases.

According to the World Health Organization (WHO), in 2008 about 17.3 million people died from cardiovascular diseases; this is 30% of the total number of deaths in the world [13]. Of these, 7.3 million are deaths from coronary heart disease and its acute manifestations – heart attacks; 6.2 million are deaths from stroke [14]. Both develop mainly due to the blockage of blood vessels that prevents the flow of blood, which occurs with atherosclerosis.

Most researchers are inclined to believe that the development of atherosclerosis is an inflammatory process in the vascular wall, in which macrophages play a key role [15]. The development of atherosclerosis mainly involves fats that are part of low and very low density lipoproteins (LDL and VLDL) [16, 17]. In the case of penetration into the artery walls, LDL and VLDL are oxidized, attracting macrophages, which normally absorb oxidized fats and transfer them to high-density lipoproteins (HDL), contributing to their utilization.

However, hyperactivation of phagocytosis of oxidized fats by macrophages is possible: so-called foam cells are formed, which continue to accumulate oxidized fats in the intracellular space, without transferring to HDL. Eventually, such macrophages die and rupture; platelet aggregation is activated, which leads to an increase in blood clotting. At the same time, previously absorbed fats are poured out, which contributes to the activation of more and more macrophages. Fibrous plaques are formed, in which dead tissues accumulate; in the future, these plaques are calcified. This leads to vascular deformation and narrowing of the lumen up to complete blockage.

One of the factors contributing to the occurrence of inflammation is the inhibitory effect of TMAO on the reverse transport of cholesterol and stimulation of the expression of SRA and CD36 receptors on their outer membrane, which leads to a violation of the absorption of modified lipoproteins [3, 18, 19]. Another factor caused by TMAO is the inhibition of bile accumulation in the liver and a decrease in the expression of proteins responsible for the synthesis and transport of bile acids. Both the first and second factors are associated with the development of atherosclerosis (Fig. 7), however, the details of the mechanisms of action of TMAO on the reverse transport of cholesterol, synthesis and transport of fatty acids remain unknown.

Figure 7. The general scheme of the proposed metabolic pathway through which the microbiota affects the development of atherosclerosis [1]. Intestinal bacteria digest L-carnitine and choline, forming TMA, and then TMAO. TMAO affects the metabolism of cholesterol and sterol in macrophages, liver and intestines. It suppresses the reverse transport of cholesterol, increases the expression of SRA and CD36 macrophage receptors, promoting the formation of foam cells.Conclusion

Probably, the metabolic pathway of L-carnitine with the participation of the intestinal microbiota is the main reason for the long–noticed relationship between the abundant consumption of red meat and the occurrence of atherosclerosis.

Antibiotics that inhibit the synthesis of TMA by the intestinal flora can become a new weapon for the fight and prevention of cardiovascular diseases. In addition, the discovery of TMAO synthesis from L-carnitine casts doubt on the public's belief in the absolute harmlessness of L-carnitine for health and shows the need for its further research.

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