Z Gastroenterol 2010; 48 - G6
DOI: 10.1055/s-0030-1267705

Deficiency of phosphatidylinositol 3-kinase (PI3K) aggravates inflammation and fibrosis in experimental non alcoholic steatohepatitis but protects against bile duct ligation induced liver fibrosis in vivo

K Dostert 1, R Wiest 1, J Schölmerich 1, C Hellerbrand 1, E Gäbele 1
  • 1Department of Internal Medicine I, University Medical Center, Regensburg

Background: 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 participates in HSC proliferation and collagen expression. The aim of this study was to evaluate the role of PI3K in the development of experimental NASH and biliary fibrosis.

Methods: Female PI3K knockout mice (PI3K–/–, on a 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 (17% fat, supplemented with 1.25% cholesterol and 0.5% cholate; Matsuzawa et al. Hepatology 2007). 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 (AST, ALT) in the HF WT group, which were significantly higher in PI3K–/– mice. Hepatic mRNA expression of proinflammatory (MCP-1, TNF) and profibrogenic (Collagen I, Pai-1, TGF-β), genes was significantly induced in PI3K–/– HF mice compared to WT HF mice. Gene expression indicating oxidative stress (Nox2, p47phox) was increased in PI3K–/– mice. Elevated collagen I and α-smooth muscle actin (α-SMA) expression was evident in PI3K–/– mice. In contrast, PI3K–/– mice were protected from BDL-induced liver fibrosis indicated by lower serum transaminases (ALT, AST), lower proinflammatory (MCP-1, TNF) and profibrogenic (Collagen I, Pai-1, TGF-β) gene expression, and less fibrosis in the histology in line with decreased collagen I as well as α-SMA protein expression.

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