The liver is a key regulator of fuel utilization, and insulin acts to inhibit hepatic gluconeogenesis and activate lipogenesis, thereby preventing excessive glucose release during the fed state. Phosphatidylinositol 3-kinase (PI3K) is a key mediator of insulin signaling. PI3K is a dimer of a catalytic subunit (p110) and a regulatory subunit (p85). Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the product of PI3K, is metabolized by the lipid phosphatase PTEN. Taniguchi et al. created a liver-specific knockout of the p85α subunit in mice (L-Pik3r1KO) and found that, contrary to expectations, the knockout mice showed increased liver responsiveness to insulin and had lower circulating glucose, free fatty acids, and triglyceride concentrations than wild-type littermates. Peripheral tissue (muscle and adipose) glucose utilization was also increased in the knockout mice. Although the knockout mice showed decreased total hepatic PI3K activity and decreased abundance of the p110 subunit (p85 stabilizes p110), insulin stimulated a prolonged elevation in hepatic PIP3 abundance and higher activation of Akt, a kinase activated by PIP3, compared with wild-type mice. The increase in PIP3 abundance appeared to be due to decreased PTEN activity in the livers of the knockout mice, suggesting that the p85 subunit regulates not only the production of PIP3 but also its metabolism.
C. M. Taniguchi, T. T. Tran, T. Kondo, J. Luo, K. Ueki, L. C. Cantley, C. R. Kahn, Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN. Proc. Natl. Acad. Sci. U.S.A. 103, 12093-12097 (2006). [Abstract] [Full Text]