A novel branched galactomannoglucan from Acorus tatarinowii alleviates liver fibrosis via dual suppression of the transport of collagen and TGF-β/Smad signaling.

Macrophages can secrete various cytokines associated with liver fibrosis. Galactomannoglucan may activate macrophages. We further hypothesize that galactomanoglucan might impact liver fibrosis. Here we report a novel homogeneous branched galactomannoglucan, AW1, from Acorus tatarinowii, composed of Man, Rha, Glc, Gal, Xyl, and Ara with a molar ratio of 10.8: 0.9: 23.1: 9.2: 6.8: 7.3. AW1 has a backbone composed of alternating 1, 4-linked Glcp and 1, 4-linked Manp residues with branches at the C-6 position of 1,4, 6-linked Glcp, and terminal Xylp, and an arabinogalactan composed of Galp, Araf, and terminal T-Glcp. Interestingly, AW1 markedly inhibits transforming growth factor-β (TGF-β)-induced activation of human hepatic stellate cell (LX-2) in vitro and alleviates carbon tetrachloride (CCl₄)-induced liver fibrosis in mice upon oral administration. Mechanism studies reveal that AW1 suppresses the expression of the Trk-fused gene protein (TFG) and the secretion-defective gene (SEC), thereby attenuating the TFG/SEC trafficking pathway and ultimately blocking the transport of collagen from the endoplasmic reticulum (ER) into the Golgi apparatus (Golgi). Simultaneously, AW1 may dramatically impede the TGF-β/Smad signaling pathway. Accordingly, AW1 shows dual regulatory actions on mitigating hepatic fibrogenesis. The above evidence suggests that AW1 may be a promising lead compound for the development of new anti-liver fibrosis drugs.