The Function of AP-1 and NR1D1 as Coregulator of LXR

Abstract

Liver X receptor (LXR) α and β are nuclear receptors that regulate genes controlling lipid metabolism in numerous tissues. LXRs have been suggested as a potential therapeutic target to treat various pathological disorders that are driven by lipid metabolism. Thus numerous efforts to find ligands and modulators that have the ability to regulate LXR activity are being made to treat diseases and have been highlighted. Therefore, we aimed to identify the modulators and molecular mechanisms which regulate LXR-mediated lipid metabolism in certain tissues. We found two cases of regulating the activity of LXR in skin and liver. First, in skin, Raffinose, an oligosaccharide, activated LXR transcriptional activity and induced genes involved in LXR-mediated lipid metabolism, water transport and keratinocyte differentiation through in vitro and in vivo study. However, Raffinose is not a ligand of LXRs. To elucidate the mechanism, we focused on the correlation between LXRs and AP-1 family that plays a critical role in keratinocyte survival and differentiation. Raffinose and TO901317 induced the expression of JunD and Fra1, and increased DNA binding of c-Jun on the AP-1 response element in the promoter of involucrin and loricrin. Interestingly, LXRs also bound to AP-1 sites after treatment with Raffinose and TO901317. JunD and Fra1 enhanced transcriptional function of LXR and increased expression of genes involved in LXR-mediated lipid metabolism. Therefore, the results of the first case suggest that Raffinose inducess AP-1 family, c-Jun, JunD and Fra1, which leads to the induction of LXR signaling and stimulation of keratinocyte differentiation. Secondly, in liver, we showed that nuclear receptor subfamily 1 , group D, member1 (NR1D1) upregulated genes of LXRα and SREBP1-c and induced transcriptional acitivity of LXRα and LXRβ. In vitro screening for finding NR1D1 ligand showed that Compound1 antagonizes transcriptional activity of NR1D1. This Compound1 suppressed transcriptional function of LXR as well as protein levels of LXR and LXR-mediated lipogenic genes. Taken together, our results suggest that as transactivating coregulators of LXR, AP-1 family and NR1D1 regulate lipid metabolism in skin and liver. Our observations may help applying on treating a variety of diseases.