| Nearly every enzymatic step required for the mitochondrial beta-oxidation of saturated and unsaturated fatty acids has been associated with an inherited metabolic disorder. The current treatment involves providing the majority of dietary fat as medium even-chain triglycerides for long-chain fatty acid oxidation disorders (FOD) or restricting dietary fat for medium- and short-chain FOD. In many cases, this treatment does not prevent the progressive deterioration of cardiac, muscular and/or retinal function. An initial clinical trial, replacing trioctanoin (medium even-chain triglyceride) in the diet by triheptanoin (medium odd-chain triglyceride), has demonstrated rapid and major clinical improvements in the treatment of long-chain FOD. The beneficial effects of triheptanoin have been ascribed to the anaplerotic property of pentanoate which is oxidized to propionyl-CoA and acetyl-CoA.; Current limitations of FOD therapy are: (i) there is no parenteral form to treat acute decompensation episodes and (ii) triheptanoin therapy is not suitable for medium-chain FOD. Pentanoate is a potentially better anaplerotic treatment for FOD because it can be used for all FOD. The goal of my study is to investigate the cardiac metabolism of pentanoate and beta-ketopentanoate (BKP), which might be used to treat acute decompensation episodes in FOD patients.; Two series of experiments using a live pig heart model and labeled substrates characterized the metabolism of pentanoate: (i) [1-13C]pentanoate (assessing the contribution of pentanoate to energy metabolism) and (ii) [3,4,5- 13C3]pentanoate and beta-keto[3,4,5-13C 3]pentanoate (assessing the efficiency as anaplerotic substrates). In the concentration range investigated (up to 1.5 mM), there was no alteration in cardiovascular parameters observed. I measured the labeling of the propionyl-CoA pathway using gas chromatography-mass spectrometry methods. The calculated total anaplerosis (enrichment ratio M3 succinyl-CoA/M3 propionyl-CoA) from pentanoate and BKP ranged from 6-10% of the citric acid cycle flux. This study paves the way to the preclinical testing of anaplerotic compounds in animal models of FOD before clinical trials are planned. |
