Abstract
The naturally occurring triterpenoid betulinic acid (BA) shows pronounced polypharmacology ranging from anti-inflammatory to anti-lipogenic activities. Recent evidence suggests that rather diverse cellular signaling events may be attributed to the same common upstream switch in cellular metabolism. In this study we therefore examined the metabolic changes induced by BA (10 µM) administration, with focus on cellular glucose metabolism. We demonstrate that BA elevates the rates of cellular glucose uptake and aerobic glycolysis in mouse embryonic fibroblasts with concomitant reduction of glucose oxidation. Without eliciting signs of obvious cell death BA leads to compromised mitochondrial function, increased expression of mitochondrial uncoupling proteins (UCP) 1 and 2, and liver kinase B1 (LKB1)-dependent activation AMP-activated protein kinase. AMPK activation accounts for the increased glucose uptake and glycolysis which in turn are indispensable for cell viability upon BA treatment. Overall, we show for the first time a significant impact of BA on cellular bioenergetics which may be a central mediator of the pleiotropic actions of BA.
Highlights
Betulinic acid (3b-3-Hydroxy-lup-20(29)-en-28-oic acid; betulinic acid (BA)) is a naturally occurring pentacyclic triterpenoid with a multifaceted activity profile
We investigated the impact of the lupane-type triterpenoid BA on cellular glucose metabolism and bioenergetics in murine embryonic fibroblasts (MEF)
We show here that BA (i) decreases the oxidative capacity, (ii) elicits elevated uncoupling proteins (UCP) expression, (iii) triggers liver kinase B1 (LKB1)-dependent AMPK activation without causing cell death, and that (iii) activated AMPK accounts for the increased uptake and metabolization of glucose via glycolysis after BA treatment. (iv) BA apparently renders cells addicted to glucose
Summary
Betulinic acid (3b-3-Hydroxy-lup-20(29)-en-28-oic acid; BA) is a naturally occurring pentacyclic triterpenoid with a multifaceted activity profile. BA and Glycolysis including the nuclear factor kB - [12], the sterol regulatory element binding protein -[7], and the endothelial NO synthase pathway [5], the mitochondrial permeability transition pore (MPTP) [13], diacylglycerol acyltransferase [14], the Tgr bile acid receptor [6], lipases [15] or protein tyrosine phosphatase 1B [16] It has recently become more and more appreciated that the metabolic program is not a passive bystander but an active modulator of signal transduction and phenotype of a cell [17]. A change in the metabolic program can influence at once multiple and at first sight unrelated signaling pathways, e.g. by providing or limiting pivotal substrates for anabolism, cytoprotection or posttranslational modifications, and be seen as one central upstream determinant of cellular behavior [18]
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