The role of PI3K p110gamma in chronic liver injury

The Phosphatidyl-insitol-3-kinase (PI3K) is a central mediator in many signalling pathways, e.g. in insulin signalling and in proinflammatory signalling via mTOR. Previous studies suggested a critical role of PI3K signalling during hepatic fibrogenesis, however, the role of different PI3K p110 isoforms has not been discriminated. The aim of this project was to assess the expression and function of PI3K p110gamma in chronic liver disease with a focus on hepatic fibrosis. We found that the expression of the PI3K class 1B unit p110gamma is increased in the liver during chronic injury. Further, we found that p110gamma expression is enhanced during the activation of hepatic stellate cells (HSC), a process which plays a key role in hepatic fibrosis. We further discovered that PI3K p110gamma deficiency had divergent effects on the activation of HSC and hepatic fibrosis, respectively, in two different models for chronic liver injury. The bile duct ligation model (BDL) causes chronic injury by inducing hepatocyte apoptosis/necrosis, because of high hepatic concentrations of bile acids. Pro-inflammatory mediators lead to the activation of resident liver macrophages (i.e. Kupffer cells) and infiltrating immune cells. PI3K p110gamma deficient mice revealed significantly diminished liver fibrosis compared to wild-type (WT) mice. In a second model for chronic liver injury, a dietary model for non-alcoholic steatohepatitis (NASH), PI3K p110gamma deficiency surprisingly had no protective effect, but even aggravated liver injury. NASH is primarily caused by a dysregulation of fatty acid (FFA) metabolism, which leads to hepatic lipid accumulation. Free fatty acids then lead to the generation of reactive oxygen species (ROS) and subsequently to lipid peroxidation, which causes hepatic inflammation and fibrosis. Here, we found that PI3K p110gamma deficiency significantly enhanced hepatic FFA accumulation and ROS formation. As potential underlying cause for the enhanced FFA accumulation in the PI3K p110gamma deficient mice we identified impaired FFA transport and enhanced beta-oxidation. In conclusion, we provide experimental evidence that the effect of PI3K p110gamma varies significantly, depending on the cause of liver injury. Particularly, in a model of NAFLD PI3K p110gamma seems to inhibit hepatic steatosis, inflammation and fibrogenesis. Currently, PI3K p110gamma inhibitors are under clinical development for the treatment of inflammatory disorders and cardiovascular dysfunctions. Based on the data of the present study one has to be very cautious regarding harmful effects of a PI3K p110gamma inhibition in patients with the metabolic syndrome or known fatty liver disease, respectively.