Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

Brazilian Journal of Medical and Biological Research

J.t. Stefano¹  I.v.a. Pereira¹  M.m. Torres¹  P.m. Bida¹  A.m.m. Coelho¹  M.p. Xerfan¹  B. Cogliati¹  D.f. Barbeiro¹  D.f.c. Mazo¹  M.s. Kubrusly¹  L.a.c. D'albuquerque¹  H.p. Souza¹  F.j. Carrilho¹  C.p. Oliveira¹ 

关键词: NASH;    Fibrosis;    Mitochondrial dysfunction;    Sorafenib;   

DOI  :  10.1590/1414-431X20143962

来源: SciELO

【 摘 要 】

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.

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