Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell

Abstract

Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cells and prevents cholera toxin-induced intestinal fluid secretion in mouse closed loop models. In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators.

Alpha-Mangostin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice Partly Through Activating Adenosine 5′-Monophosphate-Activated Protein Kinase

“…NOX4 is expressed in pulmonary fibroblasts and targeting of NOX4 inhibited the fibrotic process in experimental PF (Chan et al, 2009; Hecker et al, 2009). AMPK is a metabolic regulator, the activation of it exhibits improvement in metabolic disorders and prevention of organ dysfunction during pulmonary diseases (Myerburg et al, 2010; Muanprasat et al, 2013; Zhao et al, 2014; Malik et al, 2015). What’s more, several studies have demonstrated that activation of AMPK effectively inhibited the over-expression of NOX4 in activated lung fibroblasts (Park et al, 2012; Jian et al, 2013; Li et al, 2015; Lu et al, 2015).…”

Whey protein sweetened with Stevia rebaudiana Bertoni (Bert.) increases mitochondrial biogenesis markers in the skeletal muscle of resistance-trained rats

“…Thus, the improvement in physical performance, induced by the addition of S. rebaudiana to the whey protein supplement, maybe due to other mechanisms than its antioxidant activity. Recent studies have shown that compounds extracted from the leaves of S. rebaudiana stimulate the activation of AMPK, which has an important role during exercise [35, 36]. However, this protein seems to be preferentially activated by endurance, rather than resistance, exercise [37].…”

Diet supporting therapy for inflammatory bowel diseases

“…Activated AMPK in turn mediated an increase in Caudal type homebox 2 (CDX2) expression, which in turn is a transcriptional factor responsible for intestinal epithelial cells differentiation [ 65 ]. AMPK is an energy metabolism regulator having an important role in maintaining metabolic homeostasis [ 66 , 67 ]. It influences the epithelial barrier by differentiating, forming and maintaining it.…”