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

Eun Jin Kim, Young Sil Yoon, Suckchang Hong, Ho Young Son, Tae Young Na, Min Ho Lee, Hyun Jin Kang, Jinyoung Park, Won Jea Cho, Sang Gun Kim, Seung Hoi Koo, Hyeung geun Park, Mi Ock Lee

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)1379-1388
Number of pages10
JournalHepatology
Volume55
Issue number5
DOIs
Publication statusPublished - 2012 May

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis'. Together they form a unique fingerprint.

  • Cite this

    Kim, E. J., Yoon, Y. S., Hong, S., Son, H. Y., Na, T. Y., Lee, M. H., Kang, H. J., Park, J., Cho, W. J., Kim, S. G., Koo, S. H., Park, H. G., & Lee, M. O. (2012). Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis. Hepatology, 55(5), 1379-1388. https://doi.org/10.1002/hep.25529