Deficiency of phosphatidylinositol 3-kinase (PI3K) aggravates hepatic inflammation and fibrosis in experimental NASH but protects against bile duct ligation induced liver fibrosis

Aims: Non alcoholic steatohepatitis (NASH) leads to liver fibrosis characterized by activation of hepatic stellate cells (HSC) and enhanced collagen expression. We were able to show that PI3K, an ubiquitary heterodimeric lipid kinase, participates in HSC proliferation and collagen expression. Therefore, the aim of this study was to evaluate the role of PI3K in experimental NASH and biliary fibrosis. Methods: PI3K knockout mice (PI3K-/-, C57Bl/6 background) and C57Bl/6 wild-type control mice (WT) were allocated to 4 experimental groups (n=6) receiving either standard chow (SC) or a high fat (HF) diet according. In addition, bile duct ligation (BDL) and sham operations were performed. Results: Histological analysis revealed hepatic steatosis, inflammation and fibrosis in WT mice receiving a HF fat diet. However, these histological features of NASH were more pronounced PI3K-/- mice. Serum analysis showed elevated liver enzymes in the HF WT group, which were significantly higher in PI3K-/- mice. Hepatic mRNA expression of proinflammatory and profibrogenic genes was significantly induced in PI3K-/- HF mice compared to WT HF mice, as was expression of TLR4 and -9. Accordingly, elevated collagen I protein and alpha-smooth muscle actin (SMA) expression was evident. Furthermore, gene expression indicating oxidative stress was increased in PI3K-/- mice. In contrast, PI3K-/- mice were protected from BDL-induced liver injury indicated by lower serum transaminases, as well as decreased proinflammtory and profibrogenic gene expression, and less fibrosis. Interestingly, increased hepatic expression of PI3K p110 gamma was deteced in WT mice following BDL but not in mice with NASH. Conclusion: PI3K deficiency differently affects hepatic inflammation and fibrosis, depending on the type of injury and the predominant cell-type involved. These differences may have implications with regards to diagnosis and therapy of (fibrosis progression in) non-alcoholic liver disease.

NASH - PI3-kinase - liver fibrosis - steatosis