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 (IC 50 = 805 nM) of the carnitine palmitoyltransferase isoenzyme, located on the inner side of the mitochondrial inner membrane (CPT 2 ). The activity of the carnitine palmitoyltransferase isoenzyme located on the mitochondrial outer membrane inhibitable by malonyl-CoA (IC 50 = 19 μ M), was not inhibited by 0.8 μM l -aminocarnitine. Both in vitro and in vivo effects of l -aminocarnitine suggest that the substance has a specific and potent inhibitory action on CPT 2 . 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 CPT 2 inhibition. A markedly altered lipid metabolism was observed.