There is increasing evidence that the retinoic acid receptor-related 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 serine-threonine 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-fatty-acid 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-diet-induced 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-diet-fed 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;55:1379-1388 A n increasing number of populations in the world suffer from fatty liver, which is a disease defined as hepatic fat accumulation greater than 5% of the liver wet weight. The major causes of fatty liver are obesity, diabetes, hyperlipidemia, drugs, and metabolic disorders.1 Although this relativelyAbbreviations: ACC, acetyl-CoA carboxylase; Ad-RORa, adenovirus-RORa; AICAR, aminoimidazole carboxamide ribonucleotide; AKT2, v-akt murine thymoma viral oncogene homolog 1; AMPK, adenosine monophosphate (AMP)-activated protein kinase; ATP, adenosine triphosphate; BODIPY, borondipyrromethene; CA-AMPK, constitutively active AMPK; ChIP, chromatin immunoprecipitation; CS, cholesterol sulfate; Cyp7b1, oxysterol 7a-hydroxylase; DBD, DNA binding domain; FA, fatty acid; FAS, fatty acid synthase; FFA, free fatty acid; HFD, high-fat diet; LBD, ligand binding domain; LKB1, serine-threonine kinase liver kinase B1; LXRa, liver X receptor a; LXRE, LXR response element; NADH, reduced nicotinamide adenine dinucleotide; p, phosphorylated; RORa, retinoic acid rec...
Aims: Increased hepatic oxidative stress and inflammation is the main cause of exacerbating nonalcoholic steatohepatitis (NASH). Retinoic acid-related orphan receptor a (RORa) regulates diverse target genes associated with lipid metabolism, and its expression level is low in the liver of patients with NASH. Here, we investigated the role of RORa in regulating hepatic oxidative stress and inflammation. Results: First, cholesterol sulfate (CS), an agonist of RORa, lowered oxidative stress that was induced by 1.5 mM oleic acid in the primary cultures of hepatocytes. Second, exogenously introduced RORa or CS treatment induced the mRNA level of antioxidant enzymes, superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1), through the RORa response elements located in the upstream promoters of Sod2 and Gpx1. Third, RORa significantly decreased reactive oxygen species levels and mRNA levels of tumor necrosis factor a (TNFa) and interleukin-1b that were induced by lipopolysaccharide or TNFa in Kupffer cells. Finally, the administration of JC1-40 decreased the signs of liver injury, lipid peroxidation, and inflammation in the MCD diet-induced NASH mice. Innovation and Conclusion: We showed for the first time that RORa and its ligands protect NASH in mice by reducing hepatic oxidative stress and inflammation. Further, the molecular mechanism of the protective function of RORa against oxidative stress in the liver was revealed. These findings may offer a rationale for developing therapeutic strategies against NASH using RORa ligands.
A transfer hydrogenative condensation between 2-nitroanilines and vicinal diols for the synthesis of quinoxalines, with no additional oxidant, reductant and base.
A novel enantioselective synthetic method for the construction of a quaternary carbon center from malonates via phase-transfer catalytic (PTC) alkylation has been developed. The asymmetric α-alkylation of diphenylmethyl tert-butyl α-alkylmalonates with alkylating agents under phase-transfer catalysis conditions (aq 50% KOH, toluene, 0°C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8) as PTC catalyst afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without loss of enantioselectivity. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxindole systems.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.