Caffeic acid phenethyl ester attenuates liver fibrosis via inhibition of TGF-β1/Smad3 pathway and induction of autophagy pathway

Ning Yang; Shuangsuo Dang; Juanjuan Shi; Fengping Wu; Mei Li; Xin Zhang; Yaping Li; Xiaoli Jia; Song Zhai

doi:10.1016/j.bbrc.2017.02.057

Caffeic acid phenethyl ester attenuates liver fibrosis via inhibition of TGF-β1/Smad3 pathway and induction of autophagy pathway

Biochem Biophys Res Commun. 2017 Apr 22;486(1):22-28. doi: 10.1016/j.bbrc.2017.02.057. Epub 2017 Feb 11.

Authors

Ning Yang¹, Shuangsuo Dang², Juanjuan Shi¹, Fengping Wu¹, Mei Li¹, Xin Zhang¹, Yaping Li¹, Xiaoli Jia¹, Song Zhai³

Affiliations

¹ Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
² Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China. Electronic address: [email protected].
³ Department of Infectious Diseases, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China. Electronic address: [email protected].

PMID: 28193525
DOI: 10.1016/j.bbrc.2017.02.057

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.

Keywords: Autophagy; CAPE; Hepatic stellate cells; Liver fibrosis; TGF-β1/Smad3.

MeSH terms

Actins / genetics
Actins / metabolism
Animals
Autophagosomes / drug effects
Autophagosomes / metabolism
Autophagosomes / ultrastructure
Autophagy / drug effects*
Autophagy / genetics
Blotting, Western
Caffeic Acids / pharmacology*
Carbon Tetrachloride
Cell Line
Collagen Type I / genetics
Collagen Type I / metabolism
Dose-Response Relationship, Drug
Gene Expression / drug effects
Hepatic Stellate Cells / drug effects
Hepatic Stellate Cells / metabolism
Liver Cirrhosis / chemically induced
Liver Cirrhosis / metabolism
Liver Cirrhosis / prevention & control*
Male
Matrix Metalloproteinase 2 / genetics
Matrix Metalloproteinase 2 / metabolism
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Phenylethyl Alcohol / analogs & derivatives*
Phenylethyl Alcohol / pharmacology
Phosphorylation / drug effects
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Signal Transduction / genetics
Smad3 Protein / genetics
Smad3 Protein / metabolism*
Tissue Inhibitor of Metalloproteinase-1 / genetics
Tissue Inhibitor of Metalloproteinase-1 / metabolism
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism*

Substances

Actins
Caffeic Acids
Collagen Type I
Smad3 Protein
Smad3 protein, rat
TIMP1 protein, rat
Tissue Inhibitor of Metalloproteinase-1
Transforming Growth Factor beta1
smooth muscle actin, rat
Carbon Tetrachloride
Matrix Metalloproteinase 2
caffeic acid phenethyl ester
Phenylethyl Alcohol