Beneficial
Effect of Betulinic Acid on Hyperglycemia
via Suppression of Hepatic Glucose Production
- Publication date
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Abstract
The inhibitory effect of betulinic
acid (BA) on hepatic glucose
production was examined in HepG2 cells and high fat diet (HFD)-fed
ICR mice. BA significantly inhibited the hepatic glucose production
(HGP) and gene expression levels of PGC-1α, PEPCK, and G6Pase.
BA activated AMPK and suppressed the expression level of phosphorylated
CREB. These effects were all abolished in the presence of compound
C (an AMPK inhibitor). Moreover, inhibition of AMPK by overexpression
of dominant negative AMPK prevented BA from suppression of HGP, indicating
that the inhibitory effect of BA on HGP is AMPK-dependent. In addition,
BA markedly phosphorylated CAMKK, and phosphorylation of AMPK and
ACC, and suppression of HGP were all reversed in the presence of STO-609
(a CAMKK inhibitor), suggesting that CAMKK is an upstream kinase for
AMPK. In an animal study, HFD-fed ICR mice were orally administered
with 5 or 10 mg of BA per kg (B5 and B10) for three weeks. Plasma
glucose, triglyceride, and the insulin resistance index of the B10
group were decreased by 34%, 59%, and 38%, respectively. In a pyruvate
tolerance test, pyruvate-induced glucose excursion was decreased by
27% when mice were pretreated with 10 mg/kg of BA. In summary, BA
effectively ameliorates hyperglycemia through inhibition of hepatic
gluconeogenesis via modulating the CAMKK-AMPK-CREB signaling pathway