Metabolic effects of p‐coumaric acid in the perfused rat liver

Abstract

The p-coumaric acid, a phenolic acid, occurs in several plant species and, consequently, in many foods and beverages of vegetable origin. Its antioxidant activity is well documented, but there is also a single report about an inhibitory action on the monocarboxylate carrier, which operates in the plasma and mitochondrial membranes. The latter observation suggests that p-coumaric acid could be able to inhibit gluconeogenesis and related parameters. The present investigation was planned to test this hypothesis in the isolated and hemoglobin-free perfused rat liver. Transformation of lactate and alanine into glucose (gluconeogenesis) in the liver was inhibited by p-coumaric acid (IC50 values of 92.5 and 75.6 microM, respectively). Transformation of fructose into glucose was inhibited to a considerably lower degree (maximally 28%). The oxygen uptake increase accompanying gluconeogenesis from lactate was also inhibited. Pyruvate carboxylation in isolated intact mitochondria was inhibited (IC50 = 160.1 microM); no such effect was observed in freeze-thawing disrupted mitochondria. Glucose 6-phosphatase and fructose 1,6-bisphosphatase were not inhibited. In isolated intact mitochondria, p-coumaric acid inhibited respiration dependent on pyruvate oxidation but was ineffective on respiration driven by succinate and beta-hydroxybutyrate. It can be concluded that inhibition of pyruvate transport into the mitochondria is the most prominent primary effect of p-coumaric acid and also the main cause for gluconeogenesis inhibition. The existence of additional actions of p-coumaric acid, such as enzyme inhibitions and interference with regulatory mechanisms, cannot be excluded.

Chemical Characterization of a Hypoglycemic Extract From Cucurbita Ficifolia Bouche That Induces Liver Glycogen Accumulation in Diabetic Mice.

“…The antioxidant activity reported for p-coumaric acid could help reduce oxidative stress and, consequently, the liver cellular damage (Pereira et al, 2009). In addition, it is likely that p-coumaric acid in the extract inhibits gluconeogenesis in the liver by inhibiting pyruvate transport into the mitochondria, as reported Lima et al (2006). Other of the major compounds of C. ficifolia extract, salicin, also could contribute to the liver-protective effect due its reported neuroprotective and anti-inflammatory activity.…”

Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling

“…While several studies have shown that chemical inhibition of MPC activity decreases liver glucose production (Lima et al, 2006; Martin-Requero et al, 1986; Rognstad, 1983; Thomas and Halestrap, 1981) other studies using small molecule inhibitors of the MPC (Rognstad, 1983) or hepatocytes expressing a hypomorphic MPC2 allele (Vigueira et al, 2014), failed to demonstrate a strong effect of MPC impairment on gluconeogenesis. Our studies may explain a lack of effect of MPC inhibition on gluconeogenesis by elucidating a compensatory pathway that is operant when mitochondrial pyruvate flux is impaired.…”

The actions of fisetin on glucose metabolism in the rat liver

“…Inhibition of pyruvate transport into the mitochondria diminishes glucose synthesis from substrates such as lactate and alanine as amply demonstrated in experiments with the classical inhibitor of pyruvate transport cyano-4-hydroxycinnamic acid 33 and also in experiments with p-coumaric acid. 34 Lactate must be first transformed into pyruvate before entering the gluconeogenic pathway. Inhibition of pyruvate transport limits the availability of this compound to the intramitochondrial pyruvate carboxylase which is by far the most important regulatory enzyme, as can be deduced from its flux control coefficient (between 56 and 75%) that greatly surpasses those ones of the other enzymes including phosphoenolpyruvate carboxykinase (between 0.2 and 5%).…”