The Role of PI3K p110gamma in chronic liver injury

Phosphatidyl-insitol–3-kinase (PI3K) is a central mediator in many signaling pathways, e.g. insulin signaling and in pro-inflammatory signaling via mTOR. Previous studies suggested a critical role of PI3K signaling during hepatic fibrogenesis, however, the role of different PI3K p110 isoforms has not been discriminated.

The aim of this study was to assess the expression and function of the PI3K class 1B unit p110gamma in chronic liver disease.

Methods and Results: Hepatic PI3K p110gamma Expression is increased in murine models of liver fibrosis as well as in patients with chronic liver diseases. In the bile duct-ligation model PI3K p110gamma deficient (PI3K-/-) mice revealed significantly diminished liver fibrosis compared to wild-type (WT) mice. In contrast, PI3K-/- mice had significantly more hepatic inflammation and fibrosis in a dietary NASH-model than WT-mice. Here, PI3K-/- mice revealed more hepatic steatosis, more accumulation of free fatty acids, beta-oxidation and oxidative stress. Also in an in vitro model of hepatocellular lipid accumulation pharmacological inhibition of PI3K p110gamma caused higher free fatty acids and triglyceride levels in primary hepatocytes in vitro. Further, we found that pharmacological inhibition of PI3K p110gamma expression or suppression of PI3K p110gamma by siRNA blocked the pro-fibrogenic effects of free fatty acid stimulation on activated hepatic stellate cells (HSCs).

Conclusions: The effect of PI3K p110gamma varies significantly, depending on the cause of liver injury. Particularly, in NAFLD PI3K p110gamma seems to inhibit hepatic steatosis, inflammation and fibrogenesis. In addition to its known effect on G-receptor coupled signalling this study demonstrates so far unknown effects of this PI3K class 1B unit on lipid-metabolism in hepatocytes and lipid-induced signalling in activated HSCs.