The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD)

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.

Keywords: L-carnitine; NAFLD; NASH; Non-Alcoholic Fatty Liver Disease; Non-Alcoholic Steatohepatitis; acetyl-carnitine; cirrhosis; fatty acid transport; fatty liver; liver health.

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.

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 export of acetyl-CoA, if not used for oxidative phosphorylation or ketone production. Figure created in BioRender.com.

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 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 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 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].