Involvement of Hepatic Stimulator Substance in Experimentally Induced Fibrosis and Cirrhosis in the Rat

Abstract

Liver fibrosis results from sustained wound healing response to chronic liver injury. Liver cirrhosis, the end stage of the fibrotic process, is characterized by disruption of the entire liver architecture and reduced hepatocyte regenerative ability. Hepatic stimulator substance (HSS) is a liver-specific growth factor triggering hepatocyte proliferation in vitro and in vivo. Previous studies have indicated the involvement of HSS in animal models of acute liver injury. The aim of the present study was to investigate the involvement of HSS in the process of fibrosis and cirrhosis induction. Liver fibrosis and cirrhosis were induced in rats by thioacetamide (TAA) administration (300 mg/l) in the drinking water for 3 months, and animals were killed at 0, 1, 2, and 3 months of treatment. TAA administration resulted in progressively increasing liver fibrosis, leading to the onset of cirrhosis at the end of the experimental time. HSS was continuously produced during the course of fibrosis and cirrhosis induction, peaking at the 2nd month of TAA treatment, coinciding with markers of hepatic proliferative capacity, as thymidine kinase activity and DNA biosynthesis. Significantly reduced HSS activity was noted in cirrhotic liver (3rd month). In this case, the exogenous HSS administration during the 3rd month of TAA treatment suppressed the onset of liver cirrhosis, stimulating the hepatic regenerative capacity. Our data indicate the active participation of HSS in the process of fibrosis and cirrhosis induction post-TAA treatment in rats, suggesting also the beneficial effect of HSS treatment against cirrhosis induction with future possible clinical implications.

Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease

“…Studies carried out in vivo [20] and in vitro models [4] reported the role of several cytokines produced by the hepatocyte in the activation of hepatic stellate cells [21]. More recently extensive evidence was provided on the events associated with the hepatic lipotoxicity [22] with the hepatocyte as the main target of the so called "lipoapoptosis" [23].…”

Platelet-Activating Factor Involvement in Thioacetamide-Induced Experimental Liver Fibrosis and Cirrhosis

“…They had free access to food and water, were kept in an airconditioned room at 21°C with a 12/12-h light/dark cycle and handled humanely in accordance with European Union Dig Dis Sci (2010) 55:276-284 277 Directive 609/86 for care and use of laboratory animals. Induction of liver fibrosis was performed by administration of TAA in drinking water (300 mg/l) during a three-month period, as previously described [12,42]. The animals were sacrificed one, two, and three months from the onset of TAA administration.…”

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

“…In practice, administration of an HSS-bearing plasmid by hydrodynamic tail vein injection protects mice from hepatic failure, implying its potential role in clinical application. It has been demonstrated that alterations in HSS gene expression could be observed in relation to pathological states, such as acute liver failure (Li et al, 2011), liver cirrhosis (Gribilas et al, 2009), and hepatocellular carcinoma (Thasler et al, 2005;Dayoub et al, 2011). HSS seems to have additional clinical implications because exogenous HSS administration to rats with thioacetamide-induced liver fibrosis/cirrhosis is able to significantly decrease fibrosis and suppress the onset of cirrhosis (Gribilas et al, 2009).…”

“…It has been demonstrated that alterations in HSS gene expression could be observed in relation to pathological states, such as acute liver failure (Li et al, 2011), liver cirrhosis (Gribilas et al, 2009), and hepatocellular carcinoma (Thasler et al, 2005;Dayoub et al, 2011). HSS seems to have additional clinical implications because exogenous HSS administration to rats with thioacetamide-induced liver fibrosis/cirrhosis is able to significantly decrease fibrosis and suppress the onset of cirrhosis (Gribilas et al, 2009). ALR is critically important for the survival of hepatocytes because of its association with the maintenance of mitochondrial stability (Thirunavukkarasu et al, 2008).…”