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Figure 1 Regulation of carbohydrate metabolism by fatty acid oxidation. Predominating pathways are represented by open arrows; inhibited pathways are represented by dotted arrows. (A) When fatty acid levels are elevated, the end products of beta-oxidation reduce the activity of pyruvate dehydrogenase, the enzyme that mediates the conversion of pyruvate to acetyl CoA and permits its entry into the Krebs cycle. As a result, oxygen-wasting fatty acid oxidation predominates, pyruvate oxidation is inhibited, and lactate accumulates with deleterious consequences. (B) Inhibiting fatty acid oxidation with ranolazine should relieve the inhibition of pyruvate dehydrogenase, promoting oxidation of glucose and lactate, which phosphorylates a given amount of ATP using less oxygen than fatty acid oxidation. In addition, the coupling of pyruvate formation via glycolysis to pyruvate oxidation in the Krebs cycle is improved so that lactate accumulation is diminished.
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