6C). Furthermore, the levels of RORα protein and pAMPK were well correlated in vivo, as the levels of RORα and pAMPK were decreased

after HFD and the decrease in pAMPK was recovered after adenovirus-mediated expression of RORα (Fig. 6). Recently, Raichur et al. showed that RORα signaling is associated with increased levels of pAMPK in skeletal muscle, which may be related to our observation. 26 Further questions, INK 128 datasheet such as the manner through which RORα activates AMPK, the molecular functions of phosphorylated RORα, and the identification of phosphorylated residues of RORα, need to be investigated in the future. Mutual antagonism

HM781-36B mw between RORα and LXRα has been addressed previously in drug metabolism and metabolic homeostasis. 24, 25 RORα up-regulates the transcriptional expression of Cyp7b1, an enzyme that is critical for the homeostasis of cholesterol, oxysterol, and bile acids, whereas LXRα suppresses the RORα-induced expression of the Cyp7b1 gene. 24, 25 Activity of the LXRα-responsive reporter gene was inhibited by cotransfection with RORα, indicating that LXRα activity is suppressed reciprocally by RORα. Here, we revealed a novel molecular mechanism of RORα-induced repression of the transcriptional function of LXRα. RORα inhibited the autoactivation cycle of transcription of LXRα, thereby decreasing the mRNA level of LXRα. Obviously,

the function of the critical LXRE located on the LXRα promoter was suppressed by RORα, which may be due to the protein–protein interaction between RORα and LXRα (Fig. 3). Additionally, RORα may repress LXR function indirectly, as it activates AMPK, pentoxifylline which inhibits LXRα. 4 The fact that known ligands of LXRα, TO901317 and 24S-hydroxycholesterol, act as inverse agonists of RORα may cause difficulties in interpreting the mutual antagonism mediated by the physical interaction of the receptors. 28, 29 The affinity of ligand–receptor binding and the intracellular availability of specific ligands may determine the mode of this cross-talk. Nevertheless, the efficient down-regulation of the function of LXRα by RORα may provide a valuable tool for restricting many pathological conditions induced by overly functional LXRα, such as hepatic steatosis. The synthetic compounds that down-regulated LXRα via RORα in this study, as well as naturally occurring flavonoids that inhibit LXRα-regulated lipogenic genes, such as naringenin, are good candidates for such therapies (Fig. 7).