Deficiency of phosphatidylinositol 3-kinase (PI3K) aggravates inflammation and fibrosis in experimental NASH in vivo

Aims: Non-alcoholic steatohepatitis (NASH) leads to liver fibrosis characterized by activation of hepatic stellate cells (HSC) and collagen expression. In vitro, we were able to show that PI3K, an ubiquitary, heterodimeric lipid kinase, participates in HSC proliferation and collagen expression (J Biol Chem 2005; 280(14): 13374–82). Further, PI3K is a key component of the insulin signalling pathway.

Therefore, the aim of this study was to evaluate the role of PI3K in the development of experimental NASH.

Methods and results: PI3K knockout mice (PI3K-/-, on a C57Bl/6 background) and C57Bl/6 wild-type control mice (WT) were randomly allocated to 4 experimental groups (n=6) receiving either standard chow (SC) or a high fat (HF) diet recently shown to induce NASH with significant fibrosis (17% fat, supplemented with 1.25% cholesterol and 0.5% cholate). As expected, histological analysis showed hepatic steatosis, inflammation and fibrosis in WT mice receiving a HF fat diet. Notably, these histological features of NASH were more pronounced in PI3K-/- mice. Similarly, serum analysis revealed elevated enzymes (AST, ALT, LDH) in the HF WT group, which were significantly higher in PI3K-/- mice. Also hepatic mRNA expression of proinflammatory (MCP-1, TNF) and profibrogenic (collagen I, Pai-1, TGF-beta, TIMP) genes as well as genes indicating oxidative stress (Nox2, p47^phox) was significantly induced in PI3K-/- HF compared to WT HF mice.

Conclusion: Our data demonstrate that deficiency of PI3K enhances proinflammatory and profibrogenic changes in experimental NASH, thereby identifying PI3K as a central mediator in the pathophysiology of NASH. Further experiments are required to elucidate the mechanism of aggravated NASH in PI3K deficient mice.

Fibrosis - Inflammation - NASH - PI3K