Feedback inhibition of the retinaldehyde dehydrogenase gene ALDH1 by retinoic acid through retinoic acid receptor alpha and CCAAT/enhancer-binding protein beta

Abstract

Aldehyde dehydrogenase 1 (ALDH1) plays a major role in the biosynthesis of retinoic acid (RA), a hormone required for several essential life processes. Recent evidence, using the aryl hydrocarbon receptor-null mouse, suggests that elevated hepatic RA down-regulates ALDH1 in a unique feedback pathway to control RA biosynthesis. To determine the mechanism of suppression of the ALDH1 gene by RA, transactivation studies were carried out in Hepa-1 mouse hepatoma cells. RA decreased expression of an ALDH1-CAT construct containing -2536 base pairs of DNA upstream of the transcription start site. Retinoic acid receptor alpha (RARalpha) transactivates the ALDH1 gene promoter through a complex with an RA response-like element (RARE) located at -91/-75 bp, which bound to the RARalpha/retinoid X receptor beta heterodimer. CCAAT/enhancer-binding protein (C/EBPbeta) also transactivates the ALDH1 gene promoter through a CCAAT box located 3' and directly adjacent to the RARE, and the ALDH1 gene is down-regulated in C/EBPbeta-null mouse liver. Exposure of Hepa-1 cells to RA results in a decrease in C/EBPbeta mRNA levels; however, there was no difference in mRNA and protein levels between wild-type and AHR-null mouse liver. These data support a model in which the RARalpha and C/EBPbeta activate the ALDH1 gene promoter through the RARE and C/EBP response elements, and in Hepa-1 cells, high levels of RA inhibit this activation by decreasing cellular levels of C/EBPbeta.