title: Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro.
abstract: Liver fibrosis is a major cause of liver failure, but treatment remains ineffective. In the present study, we investigated the mechanisms and anti-hepatofibrotic activities of asiatic acid (AA) in a rat model of liver fibrosis induced by carbon tetrachloride (CCl(4)) and in vitro in TGF-beta1-stimulated rat hepatic stellate cell line (HSC-T6). Treatment with AA significantly attenuated CCl(4)-induced liver fibrosis and functional impairment in a dosage-dependent manner, including blockade of the activation of HSC as determined by inhibiting de novo alpha smooth muscle actin (a-SMA) and collagen matrix expression, and an increase in ALT and AST (all p<0.01). The hepatoprotective effects of AA on fibrosis were associated with upregulation of hepatic Smad7, an inhibitor of TGF-beta signaling, thereby blocking upregulation of TGF-beta1 and CTGF and the activation of TGF-beta/Smad signaling. The anti-fibrosis activity and mechanisms of AA were further detected in vitro in HSC-T6. Addition of AA significantly induced Smad7 expression by HSC-T6 cells, thereby inhibiting TGF-beta1-induced Smad2/3 activation, myofibroblast transformation, and collagen matrix expression in a dosage-dependent manner. In contrast, knockdown of Smad7 in HSC-T6 cells prevented AA-induced inhibition of HSC-T6 cell activation and fibrosis in response to TGF-beta1, revealing an essential role for Smad7 in AA-induced anti-fibrotic activities during liver fibrosis in vivo and in vitro. In conclusion, AA may be a novel therapeutic agent for liver fibrosis. Induction of Smad7-dependent inhibition of TGF-beta/Smad-mediated fibrogenesis may be a central mechanism by which AA protects liver from injury.
authors.affiliation: Institute of Medical Research, The First People's Hospital of Foshan, Foshan, Guangdong, China.
authors.forename: Li-xia
authors.initials: LX
authors.lastname: Tang
authors.forename: Rui-hua
authors.initials: RH
authors.lastname: He
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Jia-ju
authors.initials: JJ
authors.lastname: Tan
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D053978:Pentacyclic Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D024042:Collagen Type I; D053978:Pentacyclic Triterpenes; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C017032:asiatic acid; D002251:Carbon Tetrachloride