Deficiency of PI3K enhances inflammation and fibrosis in experimental non alcoholic steatohepatitis but attenuates bile duct ligation induced fibrosis in vivo

Aims: Activation of hepatic stellate cells (HSC) results in collagen expression and liver fibrosis. We have shown in vitro that PI3K is part of the signalling pathway which leads to HSC activation and proliferation (Gäbele et al. JBC 2005). Here, we aimed to evaluate the role of PI3K in experimental NASH and BDL induced fibrosis.

Methods and results: PI3K knockout mice (PI3K–/–) and wild-type control mice (WT; both on C57Bl/6 background) were randomly allocated to 4 experimental groups (n=6) receiving either standard chow (SC) or a high fat (HF) diet (17% fat, supplemented with 1.25% cholesterol and 0.5% cholate), which has been shown to resemble pathopyhsiological changes observed in human NASH (Matsuzawa et al. Hepatology 2007). Furthermore, BDL and sham operations were performed in PI3K–/– and WT mice. As expected, histological analysis revealed hepatic steatosis, inflammation and fibrosis in WT mice receiving HF diet. However and interestingly, these histological features of NASH were more severe in PI3K–/– mice receiving HF diet. Consistent with this, PI3K–/– mice revealed higher levels of serum transaminases and higher hepatic expression of proinflammatory (MCP-1, TNF) and profibrogenic (collagen I, Pai-1, TGF-beta, TIMP) genes, and higher hepatic collagen I protein deposition than WT mice in response to HF-feeding. Furthermore, gene expression indicative for oxidative stress (Nox2, p47^phox) was significantly increased in PI3K–/– HF mice. In contrast, in the BDL-model PI3K–/– mice displayed lower serum transaminases, lower proinflamatory and profibrogenic gene expression, and less histological fibrosis.

Conclusion: PI3K deficiency differently affects hepatic inflammation and fibrosis depending on the type of injury. Further experiments are required to elucidate the molecular mechanism underlying the diverse PI3K effects.