Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis

There is increasing evidence that the retinoic acid receptorrelated orphan receptor a (RORa) plays an important role in the regulation of metabolic pathways, particularly of fatty acid and cholesterol metabolism; however, the role of RORa in the regulation of hepatic lipogenesis has not been studied. Here, we report that RORa attenuates hepatic steatosis, probably via activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and repression of the liver X receptor a (LXRa). First, RORa and its activator, cholesterol sulfate (CS), induced phosphorylation of AMPK, which was accompanied by the activation of serinethreonine kinase liver kinase B1 (LKB1). Second, the activation of RORa, either by transient transfection or CS treatment, decreased the TO901317-induced transcriptional expression of LXRa and its downstream target genes, such as the sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthase. RORa interacted physically with LXRa and inhibited the LXRa response element in the promoter of LXRa, indicating that RORa interrupts the autoregulatory activation loop of LXRa. Third, infection with adenovirus encoding RORa suppressed the lipid accumulation that had been induced by a free-fattyacid mixture in cultured cells. Furthermore, we observed that the level of expression of the RORa protein was decreased in the liver of mice that were fed a high-fat diet. Restoration of RORa via tail-vein injection of adenovirus (Ad)-RORa decreased the high-fat-dietinduced hepatic steatosis. Finally, we synthesized thiourea derivatives that activated RORa, thereby inducing activation of AMPK and repression of LXRa. These compounds decreased hepatic triglyceride levels and lipid droplets in the high-fat-dietfed mice. Conclusion: We found that RORa induced activation of AMPK and inhibition of the lipogenic function of LXRa, which may be key phenomena that provide the beneficial effects of RORa against hepatic steatosis. (HEPATOLOGY 2012;)