Inactivation of cardiac
pyruvate dehydrogenase complex (PDC) after prolonged
starvation and in response to
hyperthyroidism is associated with enhanced
protein expression of
pyruvate dehydrogenase kinase (PDK)
isoform 4. The present study examined the potential role of
peroxisome-proliferator-activated receptor alpha (
PPARalpha) in adaptive modification of cardiac PDK4
protein expression after
starvation and in
hyperthyroidism. PDK4
protein expression was analysed by immunoblotting in homogenates of hearts from fed or 48 h-starved rats, rats rendered
hyperthyroid by
subcutaneous injection of tri-iodothyronine and a subgroup of euthyroid rats maintained on a high-fat/
low-carbohydrate diet, with or without treatment with the
PPARalpha agonist
WY14,643. In addition, PDK4
protein expression was analysed in hearts from fed, 24 h-starved or 6 h-refed wild-type or
PPARalpha-null mice.
PPARalpha activation by
WY14,643 in vivo over the timescale of the response to
starvation failed to up-regulate cardiac PDK4
protein expression in rats maintained on standard diet (
WY14,643, 1.1-fold increase;
starvation, 1.8-fold increase) or influence the cardiac PDK4 response to
starvation. By contrast,
PPARalpha activation by
WY14,643 in vivo significantly enhanced cardiac PDK4
protein expression in rats maintained on a high-fat diet, which itself increased cardiac PDK4
protein expression.
PPARalpha deficiency did not abolish up-regulation of cardiac PDK4
protein expression in response to
starvation (2.9-fold increases in both wild-type and
PPARalpha-null mice).
Starvation and
hyperthyroidism exerted additive effects on cardiac PDK4
protein expression, but
PPARalpha activation by
WY14,643 did not influence the response of cardiac PDK4
protein expression to
hyperthyroidism in either the fed or starved state. Our data support the hypothesis that cardiac PDK4
protein expression is regulated, at least in part, by a
fatty acid-dependent,
PPARalpha-independent mechanism and strongly implicate a fall in
insulin in either initiating or facilitating the response of cardiac PDK4
protein expression to
starvation.