Hyperthyroidism facilitates cardiac fatty acid oxidation through altered regulation of cardiac carnitine palmitoyltransferase: Studies in vivo and with cardiac myocytes

The aim was to establish whether increased cardiac fatty acid oxidation in hyperthyroidism is due to direct alterations in cardiac metabolism which fa vour fatty acid oxidation and/or whether normal regulatory links between ch anges in glucose supply and fatty acid oxidation are dysfunctional. Euthyro id rats were sampled in the absorptive state or after 48 h starvation. Rats were rendered hyperthyroid by injection of tri-iodothyronine (1000 mu g/kg body wt. per day; 3 days). We evaluated the regulatory significance of dir ect effects of hyperthyroidism by measuring rates of palmitate oxidation in the absence or presence of glucose using cardiac myocytes. The results wer e examined in relation to the activity/regulatory characteristics of cardia c carnitine palmitoyltransferase (CPT) estimated by measuring rates of [H-3 ]palmitoylcarnitine formation from [H-3]carnitine and palmitoyl-CoA by isol ated mitochondria. To define the involvement of other hormones, we examined whether hyperthyroidism altered basal or agonist-stimulated cardiac cAMP c oncentrations in cardiac myocytes and whether the effects of hyperthyroidis m could be reversed by 24 h exposure to insulin infused subcutaneously (2 i . u. per day; Alzet osmotic pumps). Rates of C-14-palmitate oxidation (to ( CO2)-C-14) by cardiac myocytes were significantly increased (1.6 fold; P<0. 05) by hyperthyroidism, whereas the percentage suppression of palmitate oxi dation by glucose was greatly diminished. Cardiac CPT activities in mitocho ndria from hyperthyroid rats were 2-fold higher and the susceptibility of c ardiac CPT activity to inhibition by malonyl-CoA was decreased. These effec ts were not mimicked by 48 h starvation. The decreased susceptibility of ca rdiac CPT activities to malonyl-CoA inhibition in hyperthyroid rats was nor malised by 24 h exposure to elevated insulin concentration. Acute insulin a ddition did not influence the response to glucose in cardiac myocytes from euthyroid or hyperthyroid rats and basal and agonist-stimulated cAMP concen trations were unaffected by hyperthyroidism in vivo. The data provide insig ht into possible mechanisms by which hyperthyroidism facilitates fatty acid oxidation by the myocardium, identifying changes in cardiac CPT activity a nd malonyl-CoA sensitivity that would be predicted to render cardiac fatty acid oxidation less sensitive to external factors influencing malonyl-CoA c ontent, and thereby to favour fatty acid oxidation. The increased CPT activ ity observed in response to hyperthyroidism may be a consequence of an impa ired action of insulin but occurs through a cAMP-independent mechanism.