Role of testicular orphan receptor TR4 in atherosclerosis and regulation of TR4 activity by acetylation

Testicular Receptor 4 (TR4) is an orphan nuclear receptor whose ligand(s) is unidentified. TR4 has essential roles in growth and development, motor coordination, spermatogenesis, and metabolism. Here we revealed a novel role of TR4 in atherosclerosis. Macrophage scavenger receptor CD36 mediates foam cell formation that may result in either atherogenic or athero-protected effect in vivo. We found reduced CD36 expression with reduced foam cell formation and increased atherosclerosis lesions in mice lacking TR4 orphan nuclear receptor (TR4-/-) with atherogenic ApoE null background. Mechanistic dissection suggests that TR4 induced CD36 protein and mRNA expression via transcriptional regulation. Furthermore, stably transfected TR4-siRNA or functional TR4 cDNA in the RAW macrophage cells resulted in either decreased or increased CD36 expression with decreased or increased foam cell formation. Together, our findings suggest TR4 may function as an upstream modulator to control CD36-mediated foam cells and atherogenesis. Finding ligands of TR4 or small molecule modulators to control TR4 activity may provide a new potential therapeutic approach to battle atherosclerosis.; Coregulators and posttranslational modifications are important mechanisms by which nuclear receptor activity is regulated. Here we identified ARA55 as a corepressor for TR4. We further showed that TR4 is an acetylated protein. The analysis of TR4 mutants demonstrated that TR4 can be acetylated at lysine175 and lysine176. The positive charges of the acetylation sites may contribute to TR4 DNA binding ability. Acetylation at these residues attenuated TR4 DNA binding ability. ARAR55 increased TR4 acetylation levels, possibly due to HAT enzymes recruited to ARAR55 and TR4 complex. The balance of histone acetylation and TR4 acetylation is likely to determine the final TR4 activity. As the consequence, ARRA55 suppresses the activity of TR4, but not TR4 acetylation mutants. Thus, this study uncovered, for the first time, a mechanism by which TR4 activity was modulated by receptor acetylation.