l-Carnitine (3-hydroxy-4-trimethylaminobutyrate) is heavily marketed as a nutritional supplement, largely because of its importance in cellular energy production. l-Carnitine and its metabolite acetyl-l-carnitine are vital for shuttling acetyl groups and fatty acids into mitochondria and also as an intracellular energy reservoir of acetyl groups (see Kerner & Hoppel, 1998, for review). Acetyl-l-carnitine and other carnitine esters may also be of therapeutic value in the treatment of certain neurological disorders. Nevertheless, carnitine is not considered an essential nutrient in healthy adult humans, although there are several groups at particular risk of carnitine deficiency, including patients with liver or kidney failure, strict vegetarians, new-borns, and pregnant and nursing women. A high-affinity carnitine transporter, OCTN2, is widely expressed in mammalian tissues. Genetic defects of the OCTN2 transporter (which is a member of the organic cation transporter gene family) result in primary carnitine deficiency, which leads to skeletal and cardiac myopathy and encephalopathy (Seth et al. 1999). Various drugs (including some sulfonylureas and β-lactam antibiotics) are also substrates of OCTN2 and their side-effects may include induction of systemic carnitine deficiency (Ohashi et al. 1999). Nakanishi et al. (2001), in this issue of The Journal of Physiology, now show that a member of an entirely different transporter gene family (the sodium- and chloride-coupled amino acid transporters) also transports carnitine. This novel carnitine transporter, ATB0,+, is already known as a high-affinity transporter of cationic and neutral amino acids (Km values in the low micromolar range for many substrates) (Sloan & Mager, 1999), which may function as a major route of amino acid absorption. ATB0,+ transports both carnitine and propionyl-l-carnitine with lower affinity (Km values of the order 0.6-0.9 mm) than does OCTN2 but, unlike the latter transporter, ATB0,+ is a very poor transporter of acetyl-l-carnitine. The tissue distributions of the two cloned carnitine transporters are also distinct from one another. The ATB0,+ transporter is expressed primarily in the intestinal tract, lung and mammary gland. In contrast, OCTN2 is poorly expressed in the intestine, particularly in adult animals. It seems likely that both OCTN2 and ATB0,+ will contribute to intestinal carnitine absorption. The oral bioavailability of carnitine was only reduced by about 50 % in mice with a genetic defect in OCTN2 transport (Yokogawa et al. 1999), backing up the idea that multiple transporters absorb carnitine from the gut lumen. Carnitine is not absorbed with extreme efficiency by the mammalian intestine in vivo; indeed only about 55-85 % of dietary carnitine is absorbed in man. Studies of carnitine absorption in intact intestine (see e.g. Rebouche & Seim, 1998, for review) have revealed both active transport and putative ‘passive diffusion’ mechanisms (the latter becoming increasingly important in the adult). The active transport mechanism has functional characteristics resembling OCTN2, but it is tempting to speculate that the presumed ‘passive diffusion’ mechanism includes a major contribution from the low-affinity ATB0,+ carnitine transporter. We might also predict that carnitine absorption through ATB0,+ would achieve greater importance when OCTN2 was genetically or pharmacologically compromised and also during therapeutic supplementation with oral doses of l-carnitine. ATB0,+ is expressed in the colon as well as the small intestine and may therefore play an additional important role in scavenging carnitine from the distal intestine, by virtue of its high concentrative capacity. Most, if not all, amino acid transporter proteins in mammalian cells have relatively low specificity of binding for substrates: witness in comparison the exquisite specificity of aminoacyl tRNA synthetases for a particular amino acid. There are of course potential physiological and evolutionary benefits to this apparent ‘promiscuity’ between transporters and their substrates (see e.g. Christensen, 1990). The new study by Nakanishi and colleagues highlights a further example of this phenomenon and also throws new light on possible motifs for substrate recognition by ATB0,+. Clearly the relative position of the carboxyl and N-containing moieties is important for substrate recognition by this transporter, although the presence of an α-amino group is not absolutely essential. Such information may have important implications for our understanding of the receptor binding properties and mechanisms of amino acid transporters, and may aid rational design of more readily absorbed drugs and precursor metabolites. The ATB0,+ transporter appears likely to serve a dual role in intestinal absorption of amino acids and carnitine (although apparently not of acetyl-carnitine). Specific physiological roles for this transporter in milk formation and lung fluid homeostasis may also be revealed by further study. The extent to which different ATB0,+ substrates will compete for absorption in vivo requires more detailed investigation of the functional properties and localisation of the transporter protein. However, at first glance it appears that carnitine will face stiff competition from amino acids for absorption through ATB0,+ in the fed intestine, particularly in more proximal regions. Carnitine supplements are therefore likely to be much better absorbed on an empty stomach!
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May 19, 2004
K Horváth + 13
Open Access