High Rates of Fatty Acid Oxidation during Reperfusion of Ischemic Hearts Are Associated with a Decrease in Malonyl-CoA Levels Due to an Increase in 5′-AMP-activated Protein Kinase Inhibition of Acetyl-CoA Carboxylase

• Published in: The Journal of biological chemistry Vol. 270; no. 29; p. 17513
• Main Authors: Naomi Kudo, Amy J. Barr, Rick L. Barr, Snehal Desai, Gary D. Lopaschuk
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 21-07-1995
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.270.29.17513

We determined whether high fatty acid oxidation rates during aerobic reperfusion of ischemic hearts could be explained by
a decrease in malonyl-CoA levels, which would relieve inhibition of carnitine palmitoyltransferase 1, the rate-limiting enzyme
involved in mitochondrial uptake of fatty acids. Isolated working rat hearts perfused with 1.2 mM palmitate were subjected
to 30 min of global ischemia, followed by 60 min of aerobic reperfusion. Fatty acid oxidation rates during reperfusion were
136% higher than rates seen in aerobically perfused control hearts, despite the fact that cardiac work recovered to only 16%
of pre-ischemic values. Neither the activity of carnitine palmitoyltransferase 1, or the IC value of malonyl-CoA for carnitine palmitoyltransferase 1 were altered in mitochondria isolated from aerobic, ischemic, or
reperfused ischemic hearts. Levels of malonyl-CoA were extremely low at the end of reperfusion compared to levels seen in
aerobic controls, as was the activity of acetyl-CoA carboxylase, the enzyme which produces malonyl-CoA. The activity of 5′-AMP-activated
protein kinase, which has been shown to phosphorylate and inactivate acetyl-CoA carboxylase in other tissues, was significantly
increased at the end of ischemia, and remained elevated throughout reperfusion. These results suggest that accumulation of
5′-AMP during ischemia results in an activation of AMP-activated protein kinase, which phosphorylates and inactivates ACC
during reperfusion. The subsequent decrease in malonyl-CoA levels will result in accelerated fatty acid oxidation rates during
reperfusion of ischemic hearts.