Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds, and ammonium accumulate in body fluids of patients with disorders of propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations of propionate, 3HP, and methylcitrate persist in body fluids. We hypothesized that conserved metabolic perturbations occurring in transplanted patients result from the simultaneous presence of propionate and 3HP in body fluids. We investigated the inter-relations of propionate and 3HP metabolism in perfused livers from normal rats using metabolomic and stable isotopic technologies. In the presence of propionate, 3HP, or both, we observed the following metabolic perturbations. First, the citric acid cycle (CAC) is overloaded but does not provide sufficient reducing equivalents to the respiratory chain to maintain the homeostasis of adenine nucleotides. Second, there is major CoA trapping in the propionyl-CoA pathway and a tripling of liver total CoA within 1 h. Third, liver proteolysis is stimulated. Fourth, propionate inhibits the conversion of 3HP to acetyl-CoA and its oxidation in the CAC. Fifth, some propionate and some 3HP are converted to nephrotoxic maleate by different processes. Our data have implications for the clinical management of propionic acidemia. They also emphasize the perturbations of the liver intermediary metabolism induced by supraphysiological, i.e., millimolar, concentrations of labeled propionate used to trace the intermediary metabolism, in particular, inhibition of CAC flux and major decreases in the [ATP]/[ADP] and [ATP]/[AMP] ratios.
Keywords: 3-hydroxypropionate; liver; metabolomic and stable isotopic analysis; propionate; propionic acidemia.
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