A nuclear receptor heterodimer, CgPPAR2-CgRXR, acts as a regulator of carotenoid metabolism in Crassostrea gigas

Abstract

Nuclear receptors (NRs) are mostly ligand-activated transcription factors in animals and play essential roles in metabolism and homeostasis. The NR heterodimer composed of PPAR/RXR (peroxisome proliferator-activated receptor/retinoidXreceptor) is considered a key regulator of lipid metabolism in vertebrate. However, in molluscs, how this heterodimer is involved in carotenoid metabolism remains unclear. To elucidate how this heterodimer regulates carotenoid metabolism, we identified a PPAR gene in C. gigas, designated as CgPPAR2 (LOC105323212), and functionally characterized it using two-hybrid and reporter systems. CgPPAR2 is a direct orthologue of vertebrate PPARs and the second PPAR gene identified in C. gigas genome in addition to CgPPAR1 (LOC105317849). The results demonstrated that CgPPAR2 protein can form heterodimer with C. gigas RXR (CgRXR), and then regulate carotenoid metabolism by controlling carotenoid cleavage oxygenases with different carotenoid cleavage efficiencies. This regulation can be affected by retinoid ligands, i.e., carotenoid derivatives, validating a negative feedback regulation mechanism of carotenoid cleavage for retinoid production. Besides, organotins may disrupt this regulatory process through the mediation of CgPPAR2/CgRXR heterodimer. This is the first report of PPAR/RXR heterodimer regulating carotenoid metabolism in mollusks, contributing to a better understanding of the evolution and conservation of this nuclear receptor heterodimer.