On the rate-limiting step in the beta-oxidation of polyunsaturated fatty acids in the heart.

This study was conducted to determine if the activity of 2,4-dienoyl-CoA reductase limits the rate of cardiac beta-oxidation of highly unsaturated fatty acids. Although growth hormone treatment of hypophysectomized rats caused a 3-fold increase in the activity of 2,4-dienoyl-CoA reductase, beta-oxidation of docosahexaenoate in cardiomyocytes was not stimulated by this treatment. Since cardiomyocytes oxidized oleic acid more rapidly than docosahexaenoic acid, the utilization of energy did not limit beta-oxidation. Respiration measurements with coupled rat heart mitochondria revealed that the rates of beta-oxidation with palmitoyl-CoA and palmitoylcarnitine as substrates were virtually identical but were 3- to 4-fold higher than the rates obtained with either docosahexaenoyl-CoA or docosahexaenoylcarnitine. Although the activity of carnitine palmitoyltransferase I (CPT I) was 5 times higher with palmitoyl-CoA as substrate than with docosahexaenoyl-CoA, this reaction is only one of several that may limit the beta-oxidation of docosahexaenoic acid. Surprisingly, an incremental inhibition of CPT I resulted in a parallel inhibition of respiration supported by either palmitoyl-CoA or docosahexaenoyl-CoA. This observation agrees with the notion that CPT I may also be a regulatory enzyme in cardiac fatty acid oxidation. It is concluded that the reduction of double bonds by 2,4-dienoyl-CoA reductase does not restrict the cardiac beta-oxidation of highly unsaturated fatty acid, like docosahexaenoic acid.