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Chicken ovalbumin upstream promoter transcription factor II regulates the expression of retinoic acid receptors and retinoid X receptors in hepatocytes

Chicken ovalbumin upstream promoter transcription factor II (COUP‐TFII, nuclear receptor 2F2), a member of the nuclear receptor superfamily, has been shown to affect glucose homeostasis in genetic knockout studies. It has been suggested that COUP‐TFII may modulate the retinoid signaling pathway, which is primarily mediated by retinoic acid receptors (RARα, β, and γ) and retinoid X receptors (RXRα, β, and γ). We hypothesize that COUP‐TFII interacts with retinoid signaling system. To test it, primary rat hepatocytes were infected with recombinant β‐galactosidase or COUP‐TFII adenovirus for 18 h, and treated without or with 5 μM all‐trans retinoic acid (RA) for 6 h. The mRNA levels of RARs, RXRs and their target genes, Srebp‐1c and Pck1 were determined using real‐time PCR. COUP‐TFII over‐expression reduced the basal mRNA levels of Rara, Rxra, and Rxrb by 88%, 58%, and 88%, respectively, without affecting those of Rarb and Rxrg. RA induced the mRNA levels of Rarb and Rxrg by 10.3‐ and 6.4‐fold, respectively, with no effects on those of Rara, Rxra, and Rxrb. Interestingly, over‐expression of COUP‐TFII abolished the RA‐induced mRNA expression of Rarb, Rxrg, Srebp‐1c and Pck1. These data indicate that COUP‐TFII can negatively regulate RA signaling at least in part by inhibiting the expression of RARs and RXRs. The interaction between COUP‐TFII and retinoid signaling may play a role in controlling fuel homeostasis.