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The metabolic and genic effects induced by a 20-fold lowering of carnitine content in the heart were studied in mildronate-treated rats. In the perfused heart, the proportion of palmitate taken up then oxidized was 5-10% lower, while the triacylglycerol (TAG) formation was 100% greater than in controls. The treatment was shown to increase the maximal capacity of heart homogenates to oxidize palmitate, the mRNA level of carnitine palmitoyltransferase I (CPT-I) isoforms, the specific activity of CPT-I in subsarcolemmal mitochondria and the total carnitine content of isolated mitochondria. Concomitantly, the increased mRNA expression of lipoprotein lipase, fatty acid translocase and enzymes of TAG synthesis was associated with a 5- and 2-times increase in serum TAG and free fatty acid contents, respectively. The compartmentation of carnitine at its main functional location was expected to allow the increased CPT-I activity to ensure in vivo correct fatty acid oxidation rates. All the inductions related to fatty acid transport, oxidation and esterification most likely stem from the abundance of blood lipids providing cardiomyocytes with more fatty acids.

(1) Effects of dietary treatment of male albino rats with eicosapentaenoic acid (EPA) or docosahexaenoic acid on hepatic mitochondrial lipid metabolism have been investigated. (2) Mitochondria isolated from rats given these treatments were shown to have increased ability to respire on acyl-CoA esters in the presence of malonate. This effect was expressed with most of the long-chain acyl-CoA esters used as substrates. When malonate in the incubations was replaced with malate, mitochondria from treated animals were found to exhibit diminished rates of respiration on polyunsaturated acyl-CoA esters, in particular linolenoyl-, eicosapentaenoyl- and docosahexaenoyl-CoA. This phenomenon could not be attributed to changes in activity of carnitine palmitoyltransferase I or in peroxisomal beta-oxidation. (3) Uncoupled respiration on glutamate, malate or succinate was also affected by treatment with EPA. With liver mitochondria isolated from rats that had been treated with a omega-3 fatty acid in the fasted state, the respiratory rates were lower than those observed with mitochondria isolated from control rats. Respiratory rates with mitochondria isolated from rats given the omega-3 fatty acid in the fed state was not significantly different from control rates. (4) In rats treated with EPA in the fed state, the amount of EPA incorporated into mitochondrial lipids was markedly more increased as compared to rats given omega-3 fatty acid in the fasted state. Incorporation of dietary EPA into tissue lipids was investigated, also following mildronate treatment of rats (an inhibitor of carnitine biosynthesis). (5) A hypolipidaemic effect of dietary EPA was only observed when the fatty acid was given to fed rats. Rats treated with EPA in the fasted state, in contrast, exhibited hypoglycaemia, the hypolipidaemic effects now being absent. (6) These results suggest that hypolipidaemia is most pronounced when the metabolic state favours incorporation of dietary EPA into body lipids rather than its beta-oxidation, as mediated by the fed/fasted transition or by treatment with mildronate.

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