title: Caffeic acid phenethyl ester attenuates liver fibrosis via inhibition of TGF-β1/Smad3 pathway and induction of autophagy pathway.
abstract: Caffeic acid phenethyl ester (CAPE) has been reported to possess the hepatoprotective effect. This study was to investigate the mechanism underlying CAPE against liver fibrosis in a liver fibrosis model induced by toxic carbon tetrachloride (CCl4) in male Sprague-Dawley rats and in vitro in CAPE (5 μM, 10 μM, 15 μM) treated hepatic stellate cells (HSC-T6). We found that CAPE treatment remarkably attenuated CCl4-induced liver fibrosis by blocking the activation of HSCs as determined by the expression alternation of transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3), collage I, α-smooth muscle actin (α-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1. The hepatoprotective effects of CAPE were also associated with upregulation of autophasomes in HSCs as determined by transmission electron microscopy (TEM) detection. The in vitro study further confrimed that CAPE attenuated liver fibrogenesis via inducing authophagic markers including LC3, ATG5, Beclin 1 expressions, while inhibiting AKT/mTOR signaling in HSC-T6 cells. Thus, the protective effects of CAPE against liver fibrosis might due to the inhibition of TGF-β1/Smad3 signaling and induction of authophagy in HSCs.
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China. Electronic address: dang_1214@163.com.
authors.forename: Shuangsuo
authors.initials: S
authors.lastname: Dang
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Fengping
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China. Electronic address: songzhaiwonder@163.com.
authors.forename: Song
authors.initials: S
authors.lastname: Zhai
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002109:Caffeic Acids / Q000494:pharmacology*; D002251:Carbon Tetrachloride; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D002109:Caffeic Acids; D002251:Carbon Tetrachloride; D024042:Collagen Type I; D020778:Matrix Metalloproteinase 2; D010626:Phenylethyl Alcohol; D051900:Smad3 Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C497787:Smad3 protein, rat; C576839:TIMP1 protein, rat; C498862:Acta2 protein, rat; C055494:caffeic acid phenethyl ester
keywords: Autophagy; CAPE; Hepatic stellate cells; Liver fibrosis; TGF-β1/Smad3