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Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-I? Dependent Hepatic Stellate Cell Activation and Liver Fibrosis. Cell Mol Gastroenterol Hepatol 2019;7(1):197-209

Date

12/13/2018

Pubmed ID

30539787

Pubmed Central ID

PMC6282644

DOI

10.1016/j.jcmgh.2018.09.005

Scopus ID

2-s2.0-85057853914   34 Citations

Abstract

BACKGROUND & AIMS: Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor I? (TGF-I?) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-I? and PDGF signaling pathways.

METHODS: We performed a transcriptomic comparison of HSCs treated with TGF-I? or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators.

RESULTS: Enhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-I? but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-I?-induced fibronectin, collagen 1I?1, and I?-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-I?-treated cells. Finally, we conducted inA vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and I?-smooth muscle actin/collagen protein assays.

CONCLUSIONS: TGF-I? and PDGF share redundant and distinctA transcriptomic targets, with the former predominating in HSCA activation. The EZH2 histone methyltransferase isA preferentially involved in the TGF-I? as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-I?-treated HSCs and reduces liverA fibrosis inA vivo. The data discussed in this publication haveA been deposited in NCBI's Gene Expression Omnibus andA are accessible through GEO Series accession number GSE119606 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606).

Author List

Martin-Mateos R, De Assuncao TM, Arab JP, Jalan-Sakrikar N, Yaqoob U, Greuter T, Verma VK, Mathison AJ, Cao S, Lomberk G, Mathurin P, Urrutia R, Huebert RC, Shah VH

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Bile Ducts
Carbon Tetrachloride
Enhancer of Zeste Homolog 2 Protein
Extracellular Matrix Proteins
Hepatic Stellate Cells
Humans
Ligation
Liver Cirrhosis
Mice, Inbred C57BL
Platelet-Derived Growth Factor
Transforming Growth Factor beta
Up-Regulation