The transcription of key metabolic regulatory
enzymes in the heart is altered in the diabetic state, yet little is known of the underlying mechanisms. The aim of this study was to investigate the role of
peroxisome proliferator-activated receptor-alpha (
PPAR-alpha) in modulating cardiac
insulin-sensitive
glucose transporter (GLUT-4)
protein levels in altered metabolic states and to determine the functional consequences by assessing cardiac ischemic tolerance. Wild-type and
PPAR-alpha-null mouse hearts were isolated and perfused 6 wk after
streptozotocin administration or after 14 mo on a high-fat diet or after a 24-h fast. Myocardial d-[2-(3)H]
glucose uptake was measured during low-flow
ischemia, and differences in
GLUT-4 protein levels were quantified using Western blotting. In wild-type mice in all three metabolic states, elevated plasma
free fatty acids were associated with lower total cardiac
GLUT-4 protein levels and decreased
glucose uptake during
ischemia, resulting in poor postischemic functional recovery. Although
PPAR-alpha-null mice also had elevated plasma
free fatty acids, they had neither decreased cardiac GLUT-4 levels nor decreased
glucose uptake during
ischemia and, consequently, did not have poor recovery during reperfusion. We conclude that elevated plasma
free fatty acids are associated with increased injury during
ischemia due to decreased cardiac
glucose uptake resulting from lower cardiac
GLUT-4 protein levels, the levels of GLUT-4 being regulated, probably indirectly, through
PPAR-alpha activation.