Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway

Abstract

The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARγ siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARγ agonist, as it promoted PPARγ transactivation. The correlation between activation of PPARγ and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARγ/AMPK/ACC1 pathway.

Inhibition of the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway contributes to the anti-colitis effect of madecassic acid

“…The DSS-treated mice showed shorter colons, higher activity of myeloperoxidase (MPO), and promoted expression of Il17a and IL-17A in the colon tissues. Consistent with our previous report 16 , orally administered MA and CsA showed significant ameliorative effect on colitis, and reduced the expression of IL-17 in colon tissues ( Fig. 1a-e).…”

“…Our previous studies demonstrated that MA is a PPARγ agonist 16 . The activation of PPARγ could increase PTEN expression, and inhibit Akt phosphorylation 26 .…”

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

“…The threshold cycle numbers were obtained by MyiQ2 Detection System (Bio-Rad Laboratories, Hercules, CA, United States), and primer sequences used were listed in Table 2 . The expression of each gene was normalized to GAPDH, and calculated according to the 2 -ΔΔ Ct method ( Xu et al, 2017 ).…”

Metabolism Controls the Balance of Th17/T-Regulatory Cells

“…Another report also demonstrated that C75, which is an inhibitor of FAS, can reduce EAE disease ( 74 ). Madecassic acid has also been reported to ameliorate colitis in mice by downregulating the expression of ACC1 ( 75 ). On the other hand, it has also been reported that inhibition of ACC1 can decrease the level of FAS and increase the level of FAO ( 45 , 76 ).…”