The Importance of the Fatty Acid Transporter L-Carnitine in (NAFLD)

[madman]

Abstract: L-carnitine transports fatty acids into the mitochondria for oxidation and also buffers excess acetyl-CoA away from the mitochondria. Thus, L-carnitine may play a key role in maintaining liver function, by its effect on lipid metabolism. The importance of L-carnitine in liver health is supported by the observation that patients with primary carnitine deficiency (PCD) can present with fatty liver disease, which could be due to low levels of intrahepatic and serum levels of L-carnitine. Furthermore, studies suggest that supplementation with L-carnitine may reduce liver fat and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). L-carnitine has also been shown to improve insulin sensitivity and elevate pyruvate dehydrogenase (PDH) flux. Studies that show reduced intrahepatic fat and reduced liver enzymes after L-carnitine supplementation suggest that L-carnitine might be a promising supplement to improve or delay the progression of NAFLD.

4. The Importance of L-Carnitine Supplementation

L-carnitine supplementation has beneficial effects in patients with fatty liver disease, where elevations in high-density lipoprotein (HDL) cholesterol and reductions in liver fat have been reported [68]. L-carnitine has been shown to elevate activity and transcription of hepatic CPT I [69], leading to a reduced amount of fat in the liver [70]. Several studies have shown improvement in hepatic steatosis and cirrhosis after L-carnitine supplementation [11,50,71,72]. Furthermore, L-carnitine supplementation in humans and animal models has been shown to modulate insulin sensitivity and glucose uptake and also to have an antioxidant effect in hepatocytes [71,73,74].

4.1. L-Carnitine Supplementation is Beneficial to the Liver
4.2. Effects of L-Carnitine in Ketogenesis
4.3. L-Carnitine has a Significant Effect on Insulin and Glucose Levels


5. Summary and Conclusions

L-carnitine is a critical co-factor for transporting long-chain fatty acids into mitochondria for β-oxidation and to export excess acetyl-CoA from the mitochondrial matrix. It is relevant to liver disease in two ways. Firstly, the liver is critical in synthesizing L-carnitine, and, if diseased, L-carnitine biosynthesis is reduced which may affect whole-body fatty acid metabolism. Secondly, it might be a potential treatment for liver fat accumulation as it promotes fat oxidation and can also have beneficial effects on carbohydrate metabolism.

Treatment with L-carnitine can improve outcomes in patients with fatty liver disease (Figure 3) and has been shown to reduce ALT and AST levels, as well as liver fat accumulation. L-carnitine administration has also been shown to improve markers of glycemic control in patients with NAFLD and diabetes, most likely by regulating the ratio of acetyl-CoA/CoA in the mitochondria and thereby the PDH flux.

Patients with chronic liver disease often have reduced levels of L-carnitine. The length of acyl-carnitine species found in plasma and urine might be of importance for disease outcomes. Therefore, it might not be sufficient to solely investigate free L-carnitine, but rather all L-carnitine species should be studied. Several studies show elevated plasma long-chain acyl-carnitine but not free L-carnitine and medium-chain acyl-carnitine to be associated with fibrosis, inflammation, and cirrhosis in patients.

Larger and more comprehensive studies are needed to confirm whether L-carnitine has the beneficial effects observed in these small-scale studies in patients with NAFLD. Studies generally only measure free L-carnitine, acetyl-carnitine, or both. If in vivo imaging or biopsies are available, a more comprehensive analysis of the L-carnitine species could be possible before and after treatment with L-carnitine, to fully understand the effects of L-carnitine supplementation. Measuring L-carnitine species in a range of phenotypes might provide an insight into their use as a biomarker for liver disease.

 

[madman]

Figure 1. L-carnitine Synthesis. Endogenous L-carnitine synthesis. L-carnitine is biosynthesized from trimethyl-lysine (TML). At least four enzymes are involved in the overall biosynthesis pathway. These are trimethyl-lysine dioxygenase (TMLD), 3-hydroxy-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABA-DH) and γ-butyrobetaine dioxygenase (BBD). * The double arrow represents additional steps between HTML and γ-butyrobetaine, which are 3-hydroxy-N-trimethyllysine aldolase (HTMLA) that catalyzes 4-N-trimethylaminobutyraldehyde, which then is catalyzed by 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABA-DH) into γ-butyrobetaine.

 

[madman]

Figure 2. The L-carnitine shuttle. L-carnitine binds to acyl-CoA to help transportation to the mitochondria for β-oxidation. L-carnitine also binds to excess acetyl-CoA to be exported from the mitochondria. The outer mitochondrial membrane contains Carnitine Acyltransferase I/Carnitine Palmitoyl Transferase (CAT I/CPT I), that binds L-carnitine to acyl-CoA. Acyl-carnitine can then enter the intermembrane space of the mitochondria. The inner mitochondrial membrane contains Carnitine Acyl Carnitine Translocase (CACT), which both can transport acyl-carnitine into the mitochondrial matrix, and can export L-carnitine. The inter mitochondrial membrane also contains Carnitine Acyl Transferase II/Carnitine Palmitoyl Transferase II (CAT II/CPT II), which can separate L-carnitine from the acyl-CoA, so that it can undergo β-oxidation. L-carnitine can also bind to acetyl-CoA forming acetyl-carnitine in the mitochondrial matrix, which allows for the export of acetyl-CoA, if not used for oxidative phosphorylation or ketone production. Figure created in BioRender.com

 

[madman]

Table 1. Research studies in humans. Effects of L-carnitine supplementation in liver disease. Most results are undertaken in blood samples unless otherwise stated. ALT = alanine aminotransferase, AST = aspartate transaminase, BW = body weight, CRP = C-Reactive Protein, CT = Computed Tomography, FA = fatty acids, HbA1c = glycated hemoglobin, TNF = Tumor Necrosis Factor, LDL = low-density lipoprotein.

 

[madman]

Figure 3. Simplified schematic of the processes in Non-Alcoholic Fatty Liver Disease (NAFLD) with and without L-carnitine treatment. Left is an illustration of a fatty liver, where there is reduced oxidation of fatty acids (FA) [113], which results in accumulation of FA [114], that can lead to a less functioning liver, with elevated liver enzymes [115], possibly resulting in poor biosynthesis of L-carnitine in the liver [29], which has a negative feedback loop on the transport of FA into the mitochondria. Furthermore, patients with NAFLD have inhibited pyruvate dehydrogenase (PDH) flux [116]. Right is an illustration of a fatty liver treated with L-carnitine. L-carnitine treatment will improve the transport of long-chain FA to the mitochondria, which will increase the oxidation of FA and therefore reduce the accumulation of fat in the liver [11,71]. By having less fat in the liver, the biosynthesis of L-carnitine will not be inhibited by the liver, and it will have a positive feedback loop and improve the transport of FA to the mitochondria by L-carnitine. L-carnitine will, therefore, reduce liver enzymes and improve liver function [11]. L-carnitine treatment stimulates PDH flux by improving the acetyl-CoA/CoA ratio [101].

 

[mcs]

Abstract: L-carnitine transports fatty acids into the mitochondria for oxidation and also buffers excess acetyl-CoA away from the mitochondria. Thus, L-carnitine may play a key role in maintaining liver function, by its effect on lipid metabolism. The importance of L-carnitine in liver health is supported by the observation that patients with primary carnitine deficiency (PCD) can present with fatty liver disease, which could be due to low levels of intrahepatic and serum levels of L-carnitine. Furthermore, studies suggest that supplementation with L-carnitine may reduce liver fat and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). L-carnitine has also been shown to improve insulin sensitivity and elevate pyruvate dehydrogenase (PDH) flux. Studies that show reduced intrahepatic fat and reduced liver enzymes after L-carnitine supplementation suggest that L-carnitine might be a promising supplement to improve or delay the progression of NAFLD.




4. The Importance of L-Carnitine Supplementation

L-carnitine supplementation has beneficial effects in patients with fatty liver disease, where elevations in high-density lipoprotein (HDL) cholesterol and reductions in liver fat have been reported [68]. L-carnitine has been shown to elevate activity and transcription of hepatic CPT I [69], leading to a reduced amount of fat in the liver [70]. Several studies have shown improvement in hepatic steatosis and cirrhosis after L-carnitine supplementation [11,50,71,72]. Furthermore, L-carnitine supplementation in humans and animal models has been shown to modulate insulin sensitivity and glucose uptake and also to have an antioxidant effect in hepatocytes [71,73,74].




4.1. L-Carnitine Supplementation is Beneficial to the Liver
4.2. Effects of L-Carnitine in Ketogenesis
4.3. L-Carnitine has a Significant Effect on Insulin and Glucose Levels








5. Summary and Conclusions

L-carnitine is a critical co-factor for transporting long-chain fatty acids into mitochondria for β-oxidation and to export excess acetyl-CoA from the mitochondrial matrix. It is relevant to liver disease in two ways. Firstly, the liver is critical in synthesizing L-carnitine, and, if diseased, L-carnitine biosynthesis is reduced which may affect whole-body fatty acid metabolism. Secondly, it might be a potential treatment for liver fat accumulation as it promotes fat oxidation and can also have beneficial effects on carbohydrate metabolism.

Treatment with L-carnitine can improve outcomes in patients with fatty liver disease (Figure 3) and has been shown to reduce ALT and AST levels, as well as liver fat accumulation. L-carnitine administration has also been shown to improve markers of glycemic control in patients with NAFLD and diabetes, most likely by regulating the ratio of acetyl-CoA/CoA in the mitochondria and thereby the PDH flux.

Patients with chronic liver disease often have reduced levels of L-carnitine. The length of acyl-carnitine species found in plasma and urine might be of importance for disease outcomes. Therefore, it might not be sufficient to solely investigate free L-carnitine, but rather all L-carnitine species should be studied. Several studies show elevated plasma long-chain acyl-carnitine but not free L-carnitine and medium-chain acyl-carnitine to be associated with fibrosis, inflammation, and cirrhosis in patients.

Larger and more comprehensive studies are needed to confirm whether L-carnitine has the beneficial effects observed in these small-scale studies in patients with NAFLD. Studies generally only measure free L-carnitine, acetyl-carnitine, or both. If in vivo imaging or biopsies are available, a more comprehensive analysis of the L-carnitine species could be possible before and after treatment with L-carnitine, to fully understand the effects of L-carnitine supplementation. Measuring L-carnitine species in a range of phenotypes might provide an insight into their use as a biomarker for liver disease.

I take ~2g oral ALCAR daily, however, am concerned over the cardiovascular risk of non-dietary (supplemental) L-carnitine and the conversion in the gut to TMAO, a by-product of microbial metabolism. I tried injectable L-carnitine to bypass the gut, but it is painful.
Thoughts?

 

[Vince]

TMAO and Red Meat - What is it and is it Harmful | Chris Kresser

A recent study proposed a link between red meat consumption and an increase of TMAO in the bloodstream But how accurate is this claim? Read on for more.

chriskresser.com

Well, Kresser writes well and is persuasive with some of his argument, but again, defending a position by referencing Chris Masterjohn's "debunking" just doesn't do it for me. At least Kresser leaves the door open and says we don't yet know enough about TMAO.

 

[fifty]

I take ~2g oral ALCAR daily, however, am concerned over the cardiovascular risk of non-dietary (supplemental) L-carnitine and the conversion in the gut to TMAO, a by-product of microbial metabolism. I tried injectable L-carnitine to bypass the gut, but it is painful.
Thoughts?

I take l-carnitine powder. Is that bad?

 

[madman]

I take ~2g oral ALCAR daily, however, am concerned over the cardiovascular risk of non-dietary (supplemental) L-carnitine and the conversion in the gut to TMAO, a by-product of microbial metabolism. I tried injectable L-carnitine to bypass the gut, but it is painful.
Thoughts?

Trimethylamine-N-Oxide: Heart of the microbiotacardiovascular disease nexus?


ABSTRACT

We critically review the potential involvement of trimethylamine-N-oxide (TMAO) as a link between diet, gut microbiota, and cardiovascular disease (CVD). Generated primarily from dietary choline and carnitine by gut bacteria and hepatic flavin monooxygenase (FMO) activity, TMAO could promote cardiometabolic disease when chronically elevated. However, control of circulating TMAO is poorly understood, and diet, age, body mass, sex hormones, renal clearance, FMO3 expression, and genetic background may explain as little as 25% of TMAO variance. The basis of elevations with obesity, diabetes, atherosclerosis, or coronary heart disease (CHD) is similarly ill-defined, although gut microbiota profiles/remodeling appear critical. Elevated TMAO could promote CVD via inflammation, oxidative stress, scavenger receptor (SR) up-regulation, reverse cholesterol transport (RCT) inhibition, and cardiovascular dysfunction. However, concentrations influencing inflammation, SRs and RCT (≥100 µM) are only achieved in advanced heart failure (HF) or chronic kidney disease (CKD), and greatly exceed pathogenicity of <1-5 µM levels implied in some TMAO-CVD associations. There is also evidence CVD risk is insensitive to TMAO variance beyond these levels in omnivores and vegetarians, and that major TMAO sources are cardioprotective. Assessing available evidence suggests modest elevations in TMAO (≤10 µM) are a non-pathogenic consequence of diverse risk factors (aging, obesity, dyslipidemia, insulin-resistance/diabetes, renal dysfunction), indirectly reflecting CVD risk without participating mechanistically. Nonetheless, TMAO may surpass a pathogenic threshold as a consequence of CVD/CKD, secondarily promoting disease progression. TMAO might thus reflect early CVD risk while providing a prognostic biomarker or secondary target in established disease, although mechanistic contributions to CVD await confirmation.


Carnitine.

L-Carnitine is produced from lysine in eukaryotes and is catabolized by prokaryotic organisms [108], the latter begin able to yield TMA and malic semialdehyde via cleavage of the backbone carbon-nitrogen bond of carnitine [109]. Carnitine is an essential component of fatty acid metabolism, transporting activated long-chain fatty acyl groups into the mitochondrial matrix [110]. Similar to choline, carnitine uptake from the human small intestine is not well defined and deserves further study. Mucosal carnitine uptake appears saturated with 2 g orally administered l-carnitine [111]. Saturation is also reported with 3 x 1 g doses of carnitine, significantly elevating plasma TMAO [112], although baseline concentrations of ~35 µM in this study are over an order of magnitude higher than widely reported [59]. Consumption of ~225 g of sirloin steak (~180 mg of carnitine) transiently increases plasma TMAO concentration [20]. Prolonged daily supplementation of L-carnitine (1 g/day over more than 1 year) has been shown to increase median plasma TMAO by ~12-fold in a cohort of 9 patients with mitochondrial disorders [113]. The gut microbiota may also be able to produce γbutryobetaine from l-carnitine metabolism [108], a metabolite that bacteria can subsequently convert to TMA [95]. Collective evidence indicates that high and chronic dietary loads of carnitine are required to elevate TMAO towards pathological concentrations (>10 µM) in the long-term. Again, this may reflect substrate-driven remodeling of the gut microbiota, favoring TMAO generation (see below). Importantly, while carnitine intake increases TMAO concentrations, it reduces the risk of CVD and metabolic disorders [114], protecting against diabetes [115] and metabolic syndrome [116]. Meta-analysis indicates carnitine reduces all-cause mortality, ventricular arrhythmias, and angina symptoms in infarct patients [117]. As for choline and seafood, the proposed pathogenic role of TMAO awaits reconciliation with these observations.


CONCLUSIONS AND FUTURE DIRECTIONS

Cardiovascular disease remains the leading cause of morbidity and mortality globally, placing an enormous burden on health systems, economies, and individuals directly and indirectly affected. A proposed role for the microbiota-dependent amine TMAO as a new and modifiable determinant of CVD has thus generated much excitement. However, much remains to be clarified regarding the control of TMAO concentrations and their potential involvement in disease. Variations in human TMAO concentrations remain largely unexplained, and whether pathologically relevant elevations arise independently of other disorders is unclear. Although increased concentrations of TMAO can promote inflammation, atherosclerosis, vascular and cardiac dysfunction, and remodeling, levels inducing these effects may only be achieved in HF or CKD, or potentially CHD with comorbid conditions (or AMI). In these select settings, TMAO could play a secondary reinforcing role (Figures 2 and 4), though even this mechanistic contribution awaits confirmation. A mechanistic role for TMAO in the development of CVD also requires reconciliation with the protective effects of its dietary precursors (particularly seafood and carnitine) and the low CVD risk associated with red meat intake. Future studies should more directly test the mechanistic relevance of TMAO in CVD, clarify the effects of chronic low-grade changes in TMAO, and test whether speculative positive feedbacks (as outlined in Figure 2) might lead to progressive elevations in TMAO and dysfunction in CVD. This model is untested, though informed by the knowledge that putative effects of TMAO (e.g. inflammation, renal dysfunction, and hypoperfusion) can further enhance TMAO accumulation and observations that TMAO and renal dysfunction may up-regulate FMO3 [40], for example. Importantly, even a secondary reinforcing role supports both the utility of TMAO as a biomarker of CVD risk and as a therapeutic target in high-risk subjects with multiple comorbidities or extant CVD. How to specifically reduce TMAO without potentially detrimental effects nonetheless poses a challenge. Enhanced understanding of the specific roles of bacteria in governing TMAO concentrations and how they respond to dietary modulation, together with factors influencing FMO3 activity and other determinants of TMAO concentration is necessary before potential benefits of TMAO manipulation might be realized in select disease settings.