Computer simulation of metabolism in palmitate-perfused rat heart. III. Sensitivity analysis.

The behavior of a computer model of metabolism in glucose- and palmitate-perfused rat hearts was interpreted by sensitivity analysis to explain why the heart preferentially utilizes fatty acids as fuel even in the presence of substantial exogenous glucose. The sensitivity functions identified those metabolites and enzymes which were most important in regulating the metabolic rate and determined which enzymes set the levels of the critical metabolites. Control of the mitochondrial redox potential and the distribution of coenzyme A thioesters regulated the rate of fatty acid utilization while strong inhibition of citrate synthetase resulted in accumulation of acetyl CoA and suppression of pyruvate oxidation. Glycolysis was limited by the cytosolic ATP/ADP ratio set largely by the creatine shuttle. Metabolic control appears to be widely distributed rather than localized at "key" enzymes. Metabolite levels are usually set by enzymes controlled by modifiers whereas metabolic flux is regulated by the enzymes that produce ligands for the modifier-controlled enzymes.