Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism

Abstract

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.

Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

“…Short-chain fatty acids (SCFAs) are the important gut microbial metabolites produced from the fermentation of dietary fibers in the intestine tract. Acetate, propionate and butyrate are the principal SCFAs produced mainly by the Bacteroidetes and Firmicutes [ 53 , 54 , 55 ]. After production, these were absorbed immediately into the portal circulation and transferred to peripheral tissues including brain, where they play a crucial role in the regulation of neurological functions.…”

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…Little is known on the toxic effects of 3‐hydroxypropionic acid. There is one report, demonstrating that 3‐hydroxypropionic causes increases of CoA esters and thereby overloading of the citric acid cycle and inducing proteolysis …”

Role of Gut Microbiota-Generated Short-Chain Fatty Acids in Metabolic and Cardiovascular Health

“…Recent work has also demonstrated a role for butyrate in regulating immune response through expansion of Treg cell populations [ 23 , 24 ] adding to a body of earlier work on the role of SCFA in ameliorating the pro-inflammatory response of immune cells to antigen stimulus (reviewed in [ 25 ]). Propionate largely passes across the gut lumen, although a recent study suggests a role for propionate in intestinal gluconeogenesis [ 26 ], where it is almost quantitatively sequestrated in the liver where it may act as a gluconeogenic substrate or be oxidised [ 27 ]. Some acetate is converted to butyrate by lumenal bacteria; however, acetate largely escapes splanchnic extraction and is available to peripheral tissues where it can be used for lipogenesis in adipose tissue or oxidised by muscle [ 28 ].…”