| RORα-induced activation of AMP-activated protein kinase results in attenuation of hepatic steatosis. | |
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MedLine Citation:
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PMID: 22183856 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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An increasing volume of data indicates 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 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 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 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 Ad-RORα decreased the high-fat-diet-induced hepatic steatosis. Finally, we synthesized thiourea derivatives that activated RORα, thereby inducing the activation of AMPK and the repression of LXRα. These compounds decreased the hepatic triglyceride levels and lipid droplets in the high-fat-diet-fed mice. Conclusion: We found that RORα induced the activation of AMPK and the inhibition of the lipogenic function of LXRα, which may be key phenomena that provide beneficial effects of RORα against hepatic steatosis. (HEPATOLOGY 2011.). |
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Authors:
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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 |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-20 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Association for the Study of Liver Diseases. |
Affiliation:
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College of Pharmacy, Seoul National University, Seoul, Korea. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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