Feedback Inhibition of the Retinaldehyde Dehydrogenase GeneALDH1 by Retinoic Acid through Retinoic Acid Receptor α and CCAAT/Enhancer-binding Protein β

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 ␣ (RAR␣) transactivates the ALDH1 gene promoter through a complex with an RA response-like element (RARE) located at ؊91/؊75 bp, which bound to the RAR␣/retinoid X receptor ␤ heterodimer. CCAAT/enhancer-binding protein (C/EBP␤) also transactivates the ALDH1 gene promoter through a CCAAT box located 3 and directly adjacent to the RARE, and the ALDH1 gene is downregulated in C/EBP␤-null mouse liver. Exposure of Hepa-1 cells to RA results in a decrease in C/EBP␤ 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 RAR␣ and C/EBP␤ 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/EBP␤.

Orthogonal analysis of C/EBPβ targets in vivo during liver proliferation

“…Direct C͞EBP␤ target genes in quiescent and regenerating liver identified by this combined screening method are listed in Table 1. Three of these [Aldh1a1 (24), Pepck (25,26), and Saa1 (27-29)] have been reported to be targets of C͞EBP␤, providing support for the utility of our orthogonal analysis.…”

C/EBPα Regulates Hepatic Transcription of Hepcidin, an Antimicrobial Peptide and Regulator of Iron Metabolism

“…C/EBP␣ also specifically controls the retinaldehyde dehydrogenase gene 4 (34). In contrast, the Cyp2d5 gene is controlled by C/EBP␤ and not by C/EBP␣ (35).…”

CYP4A11 is repressed by retinoic acid in human liver cells

“…The mechanism through which ATRA antagonizes activation of gene transcription involves repression of the transcriptional activity of nuclear factors such as Nuclear Factor of Activated T-cell [38], AP-1 [37,39] or Oct4 (A) and may implicate titration of shared associated proteins or coactivators [37], dephosphorylation of a transcription factor [39] or competition for DNA binding sites [38]. In only a few of reports, RA has been shown to downregulate basal gene expression, i.e., aldehyde dehydrogenase 1 [40], or a-fetoprotein [41]. These repressive effects are mediated by transcription factors, i.e., CAAT/enhancer-binding protein b [40] or hepatocyte nuclear factor 1 and 4 [41,42].…”