title: Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Young-Sil
authors.initials: YS
authors.lastname: Yoon
authors.forename: Suckchang
authors.initials: S
authors.lastname: Hong
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Son
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Na
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Lee
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Kim
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Hyeung-geun
authors.initials: HG
authors.lastname: Park
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D000071518:Liver X Receptors; D051379:Mice; D008815:Mice, Inbred Strains; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011897:Random Allocation; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012016:Reference Values; D000072482:Retinoic Acid Receptor alpha
chemical_list: D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000249:Adenosine Monophosphate; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases