The anaplerotic potential of pentanoate and B‐ketopentanoate in pig heart in vivo

We previously showed (Roe et al., J Clin Invest 110: 259, 2002) that the cardiovascular and muscle strength status of patients with long‐chain fatty acid oxidation disorders was greatly improved by a diet therapy with triheptanoin. The benefit of the treatment was ascribed to the production of anaplerotic propionyl‐CoA from heptanoate. We hypothesized that pentanoate (as tripentanoin) and β‐ketopentanoate (as a glycerol ester) might be used for the acute treatment of patients with long‐chain or medium‐chain fatty acid oxidation defects. We investigated the metabolism and anaplerotic potential of these compounds in live pig hearts. [3,4,5‐ 13 C 3 ]Pentanoate, [1‐ 13 C]pentanoate or β‐keto‐[3,4,5‐ 13 C 3 ]pentanoate were infused at various concentrations (0 to 1.5 mM) in the coronary artery of anesthetized pigs. The uptake of pentanoate and β‐ketopentanoate increased linearly with substrate concentration, and there was no impairment of cardiac function at all concentrations infused. From the mass isotopomer distribution of intermediates of the propionyl‐CoA pathway and the citric acid cycle, we calculated the rate of anaplerosis from pentanoate and β‐ketopentanoate (6–10% of the citric acid cycle). The infusion of pentanoate or β‐ketopentanoate decreased the production of endogenous propionyl‐CoA, and thus the oxidation of proteins in the heart. Supported by NIH grants DK069752 and P01HL074237.