An Up-and Down-Regulator

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Science  25 Aug 2006:
Vol. 313, Issue 5790, pp. 1021
DOI: 10.1126/science.313.5790.1021c

The liver is a key controller 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 mediator of insulin signaling and 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 p85 subunit in mice and found that, contrary to expectations, these mice showed increased liver responsiveness to insulin and had lower circulating glucose, free fatty acids, and triglyceride concentrations than wild-type littermates. Muscle and adipose glucose utilization was also increased in the knockout mice. Although the knockout mice showed decreased hepatic PI3K activity and decreased levels of the p110 subunit (p85 stabilizes p110), insulin produced a prolonged elevation in hepatic PIP3 and a higher activation of Akt, a kinase regulated by PIP3, as compared to wild-type mice. The increase in PIP3 appeared to be due to decreased PTEN activity in the livers of the knockout mice, suggesting that p85 regulates not only the production of PIP3 but also its metabolism. — NRG

Proc. Natl. Acad. Sci. U.S.A. 103, 12093 (2006).

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