Isoform specific regulation of osteopontin by AKT2 in hepatocytes and livers

Abstract

Elevated levels of osteopontin (OPN), an inflammatory cytokine, are correlated with chronic inflammatory conditions and liver cancer. In this study, we explored the regulation of OPN in liver and hepatocytes by AKT1 vs. AKT2, the two AKT isoforms expressed in hepatocytes and livers. Using a mouse model lacking PTEN (phosphatase and tensin homologue deleted on chromosome 10), the negative regulator of phosphatidylinositol 3-kinase (PI3K)/AKT signaling, expression of secreted phosphoprotein 1 (Spp1), the gene encoding OPN, was found to be the topmost significantly upregulated gene in the liver. Using an add-back experiment in hepatocytes isolated from these mice, we show that PTEN regulates the expression of Spp1 mRNA as well as OPN protein levels. Exploring how PTEN regulates the expression of Spp1/OPN, we investigated the differential roles of AKT1 vs. AKT2 using hepatocytes isolated from mice lacking each AKT isoform in the liver. We showed here that levels of Spp1/OPN in hepatocytes are lost with deletion of Akt2 but not Akt1. Deletion of Akt2 significantly attenuated both basal expression of OPN and its response to IGF-1 stimulation. AKT1 loss, on the other hand, permitted more robust induction of OPN by IGF-1 stimulation. Furthermore, mice lacking AKT2 and PTEN exhibit significantly lower OPN expression in the liver. Together, this study showed that OPN levels are regulated by the PI3K/AKT signal in hepatocytes and that AKT2 but not AKT1 is responsible for its induction in response to stimulation of the PI3K signaling pathway.