title: Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model.
abstract: Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg(-1)·day(-1) by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: J T
authors.initials: JT
authors.lastname: Stefano
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: I V A
authors.initials: IV
authors.lastname: Pereira
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: M M
authors.initials: MM
authors.lastname: Torres
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: P M
authors.initials: PM
authors.lastname: Bida
authors.affiliation: Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: A M M
authors.initials: AM
authors.lastname: Coelho
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: M P
authors.initials: MP
authors.lastname: Xerfan
authors.affiliation: Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: B
authors.initials: B
authors.lastname: Cogliati
authors.affiliation: Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: D F
authors.initials: DF
authors.lastname: Barbeiro
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: D F C
authors.initials: DF
authors.lastname: Mazo
authors.affiliation: Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: M S
authors.initials: MS
authors.lastname: Kubrusly
authors.affiliation: Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: L A C
authors.initials: LA
authors.lastname: D'Albuquerque
authors.affiliation: Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: H P
authors.initials: HP
authors.lastname: Souza
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: F J
authors.initials: FJ
authors.lastname: Carrilho
authors.affiliation: Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: C P
authors.initials: CP
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D018834:Chaperonin 60 / Q000032:analysis / Q000235:genetics; D059305:Diet, High-Fat / Q000379:methods; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D024022:Fibrillar Collagens / Q000187:drug effects; D005982:Glutathione Transferase / Q000032:analysis / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000235:genetics; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000150:complications*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011048:Polarography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000302:isolation & purification; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics
chemical_list: D018834:Chaperonin 60; D024022:Fibrillar Collagens; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010671:Phenylurea Compounds; C501429:Ppargc1a protein, rat; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D016753:Interleukin-10; D009536:Niacinamide; D004052:Diethylnitrosamine; D000077157:Sorafenib; D005982:Glutathione Transferase; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat