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Título: Sorafenib improves liver mitochondrial dysfunction attenuating liver fibrosis in non-alcoholic steatohepatitis (NASH) model
Autor: STEFANO, Jose TadeuPEREIRA, Isabel V.COELHO, Ana Maria M.XERFAN, Mariana P.BARBEIRO, Denise F.TORRES, Mariana MacielBIDA, Patricia MartinsMAZO, Daniel F.COGLIATI, BrunoSOUZA, Heraldo PossoloD'ALBUQUERQUE, Luiz C.CARRILHO, Flair J.OLIVEIRA, Claudia P.
Citación: HEPATOLOGY, v.56, suppl.1, p.864A-864A, 2012
Resumen: Background/Aim: Mitochondria dysfunction in liver may play an important role in the induction of NASH and fibrosis. Recent evidences have shown that kinase inhibitors are able to inhibit angiogenesis, a key mechanism in fibrosis development. We investigated the role of sorafenib as an antifibrotic agent in a rodent model of NASH. Methods: Adult Sprague-Dawley rats, weighing 250-300g, were fed a choline-deficient high fat diet (CDHFD)(35% total fat, 54% trans fatty acid enriched) and simultaneously exposed to diethylnitrosamine (DEN)(100 mg/Kg) in drinking water during 6 weeks to induce NASH and fibrosis. Sorafenib group (n=10) received sorafenib 2.5 mg/kg/day; NASH group (n=10) received CDHFD plus DEN by daily gavage. Control group (n=4) was fed a standard diet. After this period the animals were sacrificed and liver tissues were collected for histologic examination, mRNA isolation and analysis of mitochondrial function. Genes related to fibrosis [matrix metalloproteinases-9 (MMP-9), tissue inhibitor of matrix metalloproteinases 1 and 2 (TIMP-1 and 2)], oxidative stress [Heat Shock Protein 60 and 90 (HSP-60 and 90)] and mitochondrial biogenesis [peroxisome proliferator-activated receptorgamma co-activator 1 α (PGC-1 α )] were evaluated by RT-qPCR method. Liver mitochondrial oxidation and phosphorylation activities were measured by polarographic method. Results: Sorafenib treatment restored the liver mitochondrial function almost similar with control group, and increased RCR and state 3 respiration in comparison to NASH group (Table 1). Besides, sorafenib upregulated PGC-1 α (p<0,001), a gene related to mitochondrial biogenesis. In the other side, TIMP-2 gene expression also was upregulated (p=0,026). There was no difference in expression of HSP-60 (p=0,447), HSP-90 (p=0,141), TIMP-1 (p=0,623) and MMP-9 (p=0,623) between both groups. All of the animals treated with sorafenib showed a significant lost weight and a decreased of fibrosis score in comparison to control (p<0.05). Conclusions: 1) Treatment with sorafenib reduced fibrosis in a rodent model of NASH; 2)Sorafenib increased mRNA expression of PGC-1α and TIMP-2. 3) Sorafenib treatment improves liver mitochondrial dysfunction. Considering that PGC1 α coordinates gene expression that stimulates mitochondrial biogenesis and the TIMP-2 abrogates endothelial cell proliferation and blocks angiogenesis, sorafenib could be used in the treatment of liver fibrosis and prevent fibrosis in this model.
Aparece en las colecciones:

Comunicações em Eventos - FM/MCM
Departamento de Clínica Médica - FM/MCM

Comunicações em Eventos - FM/MGT
Departamento de Gastroenterologia - FM/MGT

Comunicações em Eventos - HC/ICHC
Instituto Central - HC/ICHC

Comunicações em Eventos - LIM/07
LIM/07 - Laboratório de Gastroenterologia Clínica e Experimental

Comunicações em Eventos - LIM/37
LIM/37 - Laboratório de Transplante e Cirurgia de Fígado

Comunicações em Eventos - LIM/51
LIM/51 - Laboratório de Emergências Clínicas


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