Regulation of retinoid metabolism by FoxO transcription factors in the retinal pigment epithelium

Abstract

The inactivation of phosphatase and tensin homolog (PTEN) and consequent hyperactivation of Akt not only elevated a chance for tumorigenesis, but also caused age-related macular degeneration (AMD)-like retinal degeneration by triggering degeneration of retinal pigment epithelium (RPE) in mice. The activated Akt in PTEN-inactivated RPE phosphorylates various cellular proteins, including the forkhead box O (FoxO) transcription factors, to induce a series of changes in the cell.In this study, we investigated roles of FoxO in RPE at downstream of Akt. The mice lacking FoxO1,3,4 genes specifically in RPE develop retinal degeneration in a delayed time course of that observed in Pten-cko mice. We discovered short-chain alcohol dehydrogenases (ADHs) that can convert retinol (ROL) to retinal aldehyde (RAL) are targets of FoxO and were significantly reduced in Pten- and FoxO-deficient RPE. The importance of retinoid metabolism regulated by PTEN-Akt-FOXO axis in RPE was proven by the inhibition of RPE degeneration in Pten-cko retina upon dietary restriction of ROL. Together, our study not only provides a mechanistic understanding to RPE degeneration, but it further disclosed a link between retinoid metabolism.