Hepatocyte growth factor protects hepatocytes against oxidative injury induced by ethanol metabolism

Abstract

Hepatocyte growth factor (HGF) is involved in many cellular responses, such as mitogenesis and apoptosis protection; however, its effect against oxidative injury induced by ethanol metabolism is not well understood. The aim of this work was to address the mechanism of HGF-induced protection against ethanol-generated oxidative stress damage in the human cell line VL-17A (cytochrome P450 2E1/alcohol dehydrogenase-transfected HepG2 cells). Cells were pretreated with 50 ng/ml HGF for 12 h and then treated with 100 mM ethanol for 0-48 h. Some parameters of oxidative damage were evaluated. We found that ethanol induced peroxide formation (3.3-fold) and oxidative damage as judged by lipid peroxidation (5.4-fold). Damage was prevented by HGF. To address the mechanisms of HGF-induced protection we investigated the cellular antioxidant system. We found that HGF increased the GSH/GSSG ratio, as well as SOD1, catalase, and gamma-glutamylcysteine synthetase expression. To explore the signaling pathways involved in this process, VL-17A cells were pretreated with inhibitors against PI3K, Akt, and NF-kappaB. We found that all treatments decreased the expression of the antioxidant enzymes, thus abrogating the HGF-induced protection against oxidative stress. Our results demonstrate that HGF protects cells from the oxidative damage induced by ethanol metabolism by a mechanism driven by NF-kappaB and PI3K/Akt signaling.

Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice

“…Oxidative stress is one of the major inducers of hepatic apoptosis [23]. Therefore, we measured the in situ content of ROS by DCFH and DHE, as previously reported [18].…”

Alcoholic Liver Disease and the Survival Response of the Hepatocyte Growth Factor

“…HGF has shown regulate strongly GSH homeostasis by inducing the expression of -GCS (Tsuboi 1999;Valdes-Arzate et al 2009), and we are claiming that this is the main mechanism of protection against oxidative stress. In fact, c-Met KO mice are under oxidative www.intechopen.com stress due to the increment in the NADPH oxidase activity, and depletion in GSH.…”

“…It is well known that HGF/c-Met can regulate the activation of survival transcription factors such as NF-κB or Nrf2 (Gomez-Quiroz et al 2008;KaposiNovak, et al 2006;Valdes-Arzate, et al 2009) which are responsible of the expression of a wide range of antioxidant, detoxifying and antiapoptotic proteins and it has been well documented elsewhere (Fan et al 2005;Klaassen and Reisman 2010).…”

“…Analysis of the mechanism involved in the HGF-induced protection against ethanol metabolism toxicity revealed that HGF induces the activation of NF-κB, with a concomitant expression of antioxidant enzymes such as catalase, SOD1, and -GCS, as well as an elevation in GSH synthesis as a consequence of the expression of -GCS. Inhibition of NF-κB, or the main upstream activators of this transcription factor (PI3K and Akt), significantly abrogated the protective role of HGF (Gomez-Quiroz et al 2008;Valdes-Arzate et al 2009) HGF has demonstrated to increase the expression of catalse and GSHRd (Arends, et al 2008). Catalase transforms H 2 O 2 in H 2 O, and GSHRd restores GSH from GSSG (Figure 2).…”

“…In addition to the control of ROS, HGF can induce the expression of antiapoptotic proteins by the activation of survival canonical pathways for example, Akt/NF-κB, Erk1/2 or Stat3, which induce Bcl2, Bcl-XL, and Mcl-1 expression (Gomez-Quiroz et al 2008;Valdes-Arzate et al 2009), but also HGF-induction of GSH supports its antiapoptotic function, based in the fact that NAC treatment significantly reduced the Jo2-induced apoptosis in hepatocytes, and pretreatment with BSO, an inhibitor of -GCS, abrogated the protective effect of both NAC and HGF (Gomez-Quiroz et al 2008). …”