PAQRs: a counteracting force to ceramides?

Abstract

In recent years, sphingolipids have garnered increasing attention for their roles in modulating intracellular signaling events. Circulating factors associated with obesity promote excess accumulation of ceramide or glucosylceramide derivatives, which impair insulin action in peripheral tissues. In this issue, Villa et al. (p. 866) provide evidence that, in yeast, the progestin and adipoQ receptor superfamily of receptors mediate their effects via a novel ceramidase activity, generating sphingoid base as a second messenger.

Figure 1.

PAQR signaling is mediated by sphingolipid metabolism. In yeast, Izh2p leads to repression of the iron transporter FET3. This process is sequentially mediated by 1) PAQ receptors binding to their cognate ligands, 2) the cleavage of phytoceramide to regenerate phytosphingosine and fatty acid, 3) activation of Pkh1/2p by sphingoid base, 4) activation of protein kinase A (PKA) by Pkh1/2p, 5) PKA-induced inhibition of the transcriptional coactivator MSN2/4p and nuclear export of AMP kinase (preventing inhibition of the transcriptional corepressor NRG1/2p). In mammalian cells, circulating factors impair insulin sensitivity via aberrant ceramide accumulation.