Multiple retinol dehydrogenases (short‐chain dehydrogenases) and retinal dehydrogenases synthesize retinoic acid in hippocampus astrocytes

Abstract

Little direct evidence identifies hippocampus cell types and enzymes that biosynthesize all‐trans retinoic acid (atRA). We show that primary rat astrocytes, but not neurons, biosynthesize atRA using retinol dehydrogenases (RDH) of the short‐chain dehydrogenase/reductase (SDR) gene family, and retinaldehyde dehydrogenases (RALDH). Astrocytes secrete atRA into their medium; neurons sequester atRA. Neurons and astrocytes both synthesize retinyl esters (RE). atRA autoregulates its concentrations by inducing RE synthesis (lecithin:retinol acyltransferase, LRAT) and stimulating its catabolism (cytochrome P450 CYP26B1). Knockdown by RNAi indicates that RDH10, RDH2, RALDH1, 2 and 3 contribute to atRA production. Knockdown of the SDR DHRS9 increases RA synthesis ~50% thru increasing RALDH1 expression. Culture‐time dependent expression of RALDH1 and 2, RDH10, DHRS9, LRAT and CYP26B1 correlate with atRA and RE synthesis, suggesting intrinsic adaption of retinoid homeostasis. These data show that adult hippocampus astrocytes rely on multiple RDHs and RALDHs to provide a paracrine source of atRA to neurons. Observation of cross talk between DHRS9 and RALDH1 provides novel insight into regulation of RA biosynthesis. Supported by NIH grant DK36870.