title: Gene expression during chemically induced liver fibrosis: effect of halofuginone on TGF-beta signaling.
abstract: Hepatic fibrosis is associated with the activation of stellate cells (HSCs), the major source of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta), signaling via Smad3, is the most profibrogenic cytokine and the major promoter of ECM synthesis. Halofuginone, an inhibitor of liver fibrosis, inhibits TGF-beta-dependent Smad3 phosphorylation in human HSCs in culture. We have used transcriptional profiling to evaluate the effect of halofuginone on gene expression during the progression of thioacetamide (TAA)-induced liver fibrosis in the rat and have focused on genes that are associated with TGF-beta. TAA treatment causes alterations in the expression of 7% of liver genes. Halofuginone treatment prevents the changes in the expression of 41% of these genes and results in the inhibition of HSC activation and collagen synthesis. During the early stages of the disease, halofuginone affects genes involved in alcohol, lipid, protein, and phosphate metabolism and cell adhesion and, at later stages, in the cell cycle (cell development, differentiation, cell proliferation, and apoptosis). The activation of TGF-beta-dependent genes, such as tartrate-resistant acid phosphatase, its putative substrate osteopontin, stellate cell activation-association protein, and fibrillin-1, during chemically induced fibrosis is prevented by halofuginone. This study thus highlights the role of TGF-beta signaling in liver fibrosis and especially its potential for pharmacological intervention. Halofuginone, which has demonstrated efficacy and tolerance in animals and humans, could become an effective and novel therapy for liver fibrosis.
authors.affiliation: Institute of Animal Sciences, The Volcani Center, P.O. Box 6, Bet Dagan 50250, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Gnainsky
authors.forename: Z
authors.initials: Z
authors.lastname: Kushnirsky
authors.forename: G
authors.initials: G
authors.lastname: Bilu
authors.forename: Y
authors.initials: Y
authors.lastname: Hagai
authors.forename: O
authors.initials: O
authors.lastname: Genina
authors.forename: H
authors.initials: H
authors.lastname: Volpin
authors.forename: R
authors.initials: R
authors.lastname: Bruck
authors.forename: G
authors.initials: G
authors.lastname: Spira
authors.forename: A
authors.initials: A
authors.lastname: Nagler
authors.forename: N
authors.initials: N
authors.lastname: Kawada
authors.forename: K
authors.initials: K
authors.lastname: Yoshizato
authors.forename: D P
authors.initials: DP
authors.lastname: Reinhardt
authors.forename: T A
authors.initials: TA
authors.lastname: Libermann
authors.forename: M
authors.initials: M
authors.lastname: Pines
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016000:Cluster Analysis; D000078842:Cytoglobin; D018450:Disease Progression; D000071838:Fibrillin-1; D000071837:Fibrillins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D013853:Thioacetamide; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054392:Adipokines
chemical_list: D000135:Acid Phosphatase; D000970:Antineoplastic Agents; D000078842:Cytoglobin; D000071838:Fibrillin-1; D000071837:Fibrillins; D005914:Globins; D007527:Isoenzymes; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D053495:Osteopontin; D010880:Piperidines; D052999:Quinazolinones; D051899:Smad2 Protein; D051900:Smad3 Protein; D000071681:Tartrate-Resistant Acid Phosphatase; D013853:Thioacetamide; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605725:Fbn1 protein, rat; C010176:halofuginone