Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice

Abstract

Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.

TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation

“…In the current study, we demonstrated that hepatic TC and TG contents were significantly reduced after treatment with rmTSG-6, and liver histology using H&E and oil red O staining further supported the alleviation of hepatic steatosis by TSG-6 treatment. Oxidative stress plays a critical role in the pathogenesis of ALD, as numerous studies reported that formation of reactive oxygen species (ROS) are crucial for the progression of ALD (Leung and Nieto, 2013;Bankoglu et al, 2016), because they could induce hepatic steatosis, inflammatory cell infiltration, hepatomegaly, fibrosis and cirrhosis (Li et al, 2014). In this study, we found that treatment with rmTSG-6 caused significant increment in hepatic GSH level but reduction in hepatic MDA, both of which were markers of oxidative stress.…”

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

“…Oxidant stress plays a dominant role in the pathogenesis of ALD, as multiple studies have shown that generation of ROS is key for the progression of fatty liver to steatohepatitis and cirrhosis [23,24,25,26,27]. They induce pathological changes such as steatosis, inflammatory cell infiltration, hepatomegaly, fibrosis and cirrhosis [28].…”

Diet induces hepatocyte protection in fatty liver disease via modulation of PTEN signaling (Review)

“…One mechanism by which ROS exert cellular effects is through the regulation of target molecules, including PI3K/AKT/PTEN (39). The PI3K/AKT/PTEN signaling pathway protects against damaging effects originating from high levels of insulin (40). In addition, the PI3K/AKT/PTEN signaling pathway regulates factors involved in cell survival and proliferation ( Fig.…”

“…In addition, the PI3K/AKT/PTEN signaling pathway regulates factors involved in cell survival and proliferation ( Fig. 2) (40). PTEN is a dual specificity phosphatase, processing lipids and proteins, and it is a member of the protein tyrosine phosphatase family of phosphatases (41,42).…”