Betulinic acid modulates cellular metabolism in an AMP-activated kinase-dependent manner

Betulinic acid (BA), a pentacyclic triterpenoid abundantly found in nature, exerts a vast variety of bioactivities including anti-fungal, anti-bacterial, anti-inflammatory and anti-proliferative properties, both in vitro and in vivo. Recent evidence suggests that an alteration in the cellular phenotype, be it by physiological stimuli or pharmacologic intervention, is often inseparably linked with metabolic adaptations that secure sufficient supply with energy or building blocks needed for the respective cellular response. In this study we examined the metabolic changes induced by BA administration, with a main focus on cellular glucose metabolism. Using quiescent mouse embryonic fibroblasts (MEFs) as non-malignant and non-specialized cell model, we observed that BA (5 – 20µM) dose dependently elevates cellular glucose uptake, an effect which is blunted in AMP-activated kinase (AMPK) knockout (ko) MEF. Exposure to BA consistently led to a transient activation of AMPK (1 – 3 hrs) in wildtype cells, as evident by increased phosphorylation at Thr172, and subsequently to an augmented mitochondrial mass after 24 to 48 hrs in an AMPK-dependent manner. These findings are mirrored by an increase in glycolysis and a transient drop (1 – 3 hrs) followed by a sustained rise (24 – 48hrs) in ATP production by oxidative phosphorylation after exposure to BA. These findings clearly demonstrate a metabolic flavour of BA administration which has also been indicated in reports on the anti-hyperlipidemic activity of BA and which may underlie or contribute to the pleiotropic actions of BA.