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.

Alpha mangostin Inhibits Hepatic Stellate Cells Activation Through TGF-β/Smad and Akt Signaling Pathways: An in vitro Study in LX2

“…Sorafenib inhibits receptor kinase phosporilation and its downstream pathways [21,22]. Previous studies had shown that sorafenib inhibits TGF-β Smad signaling and Akt signaling [23][24][25]. Treatment with sorafenib in experimental hepatic fibrosis also showed that extracellular matrix marker such as TIMP-1 could also be decreased [26].…”

New Insight into the Anti-liver Fibrosis Effect of Multitargeted Tyrosine Kinase Inhibitors: From Molecular Target to Clinical Trials

“…The anti-fibrotic effect of sorafenib is clearly demonstrated by numerous experiment studies. In nearly all animal models of liver fibrosis, such as carbon tetrachloride (CCl 4 ), bile duct ligation (BDL), dimethylnitrosamine (DMN), diethylnitrosamine (DEN), or thioacetamide (TAA) induced models, sorafenib exhibits anti-liver fibrosis effects ( Hennenberg et al, 2009 ; Wang et al, 2010 ; Thabut et al, 2011 ; Hong et al, 2013 ; Westra et al, 2014a ; Liu et al, 2015 ; Stefano et al, 2015 ; Table 2 ).…”

Diabetes consequences in the fetus liver of the non-obese diabetic mice

“…The RNA quality and total RNA concentration were performed as reported previously. 10 Samples were kept at –80 °C until processing by quantitative RT-PCR (qRT-PCR).…”