title: Tissue lipid accumulation by L-aminocarnitine, an inhibitor of carnitine-palmitoyltransferase-2. Studies in intact rats and isolated mitochondria.
abstract: Tissues of fasted animals treated with L-aminocarnitine (L-3-amino-4-trimethylaminobutyrate) showed an accumulation of long-chain acylcarnitines and triacylglycerols. Blood levels of free fatty acids, long-chain acylcarnitines and triacylglycerol-rich lipoproteins were found to be increased, whereas glucose was reduced. The liver mitochondria isolated from rats treated with L-aminocarnitine utilized both pyruvate and succinate normally, but were not able to oxidize palmitoylcarnitine. In vitro oxidation of palmitoylcarnitine by liver mitochondria was inhibited by L-aminocarnitine in a concentration-dependent fashion in contrast to succinate and pyruvate oxidation which was not modified. L-aminocarnitine proved to be a potent and selective inhibitor (IC50 = 805 nM) of the carnitine palmitoyltransferase isoenzyme, located on the inner side of the mitochondrial inner membrane (CPT2). The activity of the carnitine palmitoyltransferase isoenzyme located on the mitochondrial outer membrane inhibitable by malonyl-CoA (IC50 = 19 microM), was not inhibited by 0.8 microM L-aminocarnitine. Both in vitro and in vivo effects of L-aminocarnitine suggest that the substance has a specific and potent inhibitory action on CPT2. Its in vivo inhibition results in a dramatic increase of long-chain acylcarnitines in various organs, that it is why this increase can be considered a very good marker of CPT2 inhibition. A markedly altered lipid metabolism was observed.
authors.affiliation: Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Chiodi
authors.forename: F
authors.initials: F
authors.lastname: Maccari
authors.forename: M T
authors.initials: MT
authors.lastname: Ramacci
mesh_terms: D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002331:Carnitine; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood; D005260:Female; D050356:Lipid Metabolism; D008316:Malonyl Coenzyme A / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010172:Palmitoylcarnitine / Q000378:metabolism; D010743:Phospholipids / Q000097:blood; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid; D014280:Triglycerides / Q000097:blood
chemical_list: D010743:Phospholipids; D011773:Pyruvates; D013386:Succinates; D014280:Triglycerides; D010172:Palmitoylcarnitine; D001622:Betaine; D008316:Malonyl Coenzyme A; D019289:Pyruvic Acid; D002784:Cholesterol; C045761:emeriamine; D019802:Succinic Acid; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine