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REV-ERB agonist

Faisal J Alibhai, Jonathan LaMarre, Cristine J Reitz, Elena V Tsimakouridze, Jeffrey T Kroetsch, Steffen-Sebastian Bolz, Alex Shulman, Samantha Steinberg, Thomas P Burris, Gavin Y Oudit, Tami A Martino
The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. Clock(Δ19/Δ19) mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness...
February 20, 2017: Journal of Molecular and Cellular Cardiology
Sadichha Sitaula, Jinsong Zhang, Fernanda Ruiz, Thomas P Burris
REV-ERBα and REV-ERBβ are heme regulated nuclear receptors that are known to regulate metabolic pathways. We previously demonstrated that treatment of mice with synthetic REV-ERB agonists suppressed plasma cholesterol levels and the hepatic levels of the rate limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-CoA reductase). Here, we characterize the role of REV-ERB on the cholesterol biosynthetic pathway in greater detail. The REV-ERB agonist SR9009 reduced plasma cholesterol levels in both wild type C57Bl/6 and low density lipoprotein receptor (LDLR) null mice as well as reducing the expression of an array of genes within the cholesterol biosynthetic pathway...
February 15, 2017: Biochemical Pharmacology
Paul G Thomes, Elizabeth Brandon-Warner, Ting Li, Terrence M Donohue, Laura W Schrum
Our data describe autophagic flux in primary rat hepatic stellate cells (rHSCs) treated with pro-fibrotic growth factor, transforming growth factor beta (TGF-β). An autophagy flux experiment determines the rate of synthesis and degradation of the autophagosome marker, LC3-II in the presence and absence of the lysosomal inhibitor bafilomcyin, which blocks LC3-II degradation in lysosomes. The effects of a test agent on LC3-II flux through the autophagic pathway is determined immunochemically by its relative amounts detected in lysates of cells treated with and without bafilomycin...
February 2017: Data in Brief
Aurore Woller, Hélène Duez, Bart Staels, Marc Lefranc
To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet...
October 18, 2016: Cell Reports
Ryota Nakazato, Shogo Hotta, Daisuke Yamada, Miki Kou, Saki Nakamura, Yoshifumi Takahata, Hajime Tei, Rika Numano, Akiko Hida, Shigeki Shimba, Michihiro Mieda, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada
Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells...
October 11, 2016: Glia
Lore Geldof, Koen Deventer, Kris Roels, Eva Tudela, Peter Van Eeno
SR9009 and SR9011 are attractive as performance-enhancing substances due to their REV-ERB agonist effects and thus circadian rhythm modulation activity. Although no pharmaceutical preparations are available yet, illicit use of SR9009 and SR9011 for doping purposes can be anticipated, especially since SR9009 is marketed in illicit products. Therefore, the aim was to identify potential diagnostic metabolites via in vitro metabolic studies to ensure effective (doping) control. The presence of SR9009 could be demonstrated in a black market product purchased over the Internet...
October 3, 2016: International Journal of Molecular Sciences
Ariadna Amador, Salvador Huitron-Resendiz, Amanda J Roberts, Theodore M Kamenecka, Laura A Solt, Thomas P Burris
The circadian clock maintains appropriate timing for a wide range of behaviors and physiological processes. Circadian behaviors such as sleep and wakefulness are intrinsically dependent on the precise oscillation of the endogenous molecular machinery that regulates the circadian clock. The identical core clock machinery regulates myriad endocrine and metabolic functions providing a link between sleep and metabolic health. The REV-ERBs (REV-ERBα and REV-ERBβ) are nuclear receptors that are key regulators of the molecular clock and have been successfully targeted using small molecule ligands...
2016: PloS One
Yoshio Inouye
Animal defense mechanisms against both endogenous and exogenous toxic compounds function mainly through receptor-type transcription factors, including the constitutive androstane receptor (CAR). Following xenobiotic stimulation, CAR translocates into the nucleus and transactivates its target genes including oxygenic and conjugative enzymes and transporters in hepatocytes. We identified subcellular localization signals in the rat CAR: two nuclear localization signals (NLS1 and 2); two nuclear export signals (NES1 and 2); and a cytoplasmic retention region...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Jiyeon Lee, Seungbeom Lee, Sooyoung Chung, Noheon Park, Gi Hoon Son, Hongchan An, Jaebong Jang, Dong-Jo Chang, Young-Ger Suh, Kyungjin Kim
Circadian rhythms, biological oscillations with a period of about 24 h, are maintained by an innate genetically determined time-keeping system called the molecular circadian clockwork. Despite the physiological and clinical importance of the circadian clock, development of small molecule modulators targeting the core clock machinery has only recently been initiated. BMAL1, a core clock gene, is controlled by a ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock...
January 15, 2016: Biochemical and Biophysical Research Communications
Norimitsu Morioka, Mizuki Tomori, Fang Fang Zhang, Munenori Saeki, Kazue Hisaoka-Nakashima, Yoshihiro Nakata
Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF)...
January 8, 2016: Biochemical and Biophysical Research Communications
Yongjun Wang, Douglas Kojetin, Thomas P Burris
REV-ERBα and REV-ERBβ are nuclear receptors that are ligand-dependent transcriptional repressors. Heme is the natural ligand for these receptors, but several synthetic agonists and antagonists have been designed recently. The gene that encodes REV-ERBα, NR1D1, is closely associated with ERBB2, the gene that encodes the HER2 oncogene, which is amplified in HER2(+) breast cancers. We examined the effect of a synthetic REV-ERB agonist, SR9011, on a range of estrogen receptor positive (ER(+)), ER(-), HER2(+), HER2(-) and triple negative breast cancer cell lines...
August 15, 2015: Biochemical Pharmacology
Sadichha Sitaula, Cyrielle Billon, Theodore M Kamenecka, Laura A Solt, Thomas P Burris
The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice...
May 8, 2015: Biochemical and Biophysical Research Communications
Subhashis Banerjee, Yongjun Wang, Laura A Solt, Kristine Griffett, Melissa Kazantzis, Ariadna Amador, Bahaa M El-Gendy, Salvador Huitron-Resendiz, Amanda J Roberts, Youseung Shin, Theodore M Kamenecka, Thomas P Burris
Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBα and β, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour...
2014: Nature Communications
Shogo Sato, Takuya Sakurai, Junetsu Ogasawara, Ken Shirato, Yoshinaga Ishibashi, Shuji Oh-ishi, Kazuhiko Imaizumi, Shukoh Haga, Yoshiaki Hitomi, Tetsuya Izawa, Yoshinobu Ohira, Hideki Ohno, Takako Kizaki
It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERBα, one of the nuclear hormone receptors with the capacity to alter clock function, is critically involved in lipid metabolism, adipogenesis, and the inflammatory response. Recent studies suggest that REV-ERBα plays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERBα in the regulation of interleukin-6 (il6) gene expression in murine macrophages...
2014: TheScientificWorldJournal
Edna Matta-Camacho, Subhashis Banerjee, Travis S Hughes, Laura A Solt, Yongjun Wang, Thomas P Burris, Douglas J Kojetin
REV-ERBα and REV-ERBβ are members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors that play important roles in the regulation of circadian physiology, metabolism, and immune function. Although the REV-ERBs were originally characterized as orphan receptors, recent studies have demonstrated that they function as receptors for heme. Here, we demonstrate that cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX (ZnPP) are ligands that bind directly to the REV-ERBs. However, instead of mimicking the agonist action of heme, CoPP and ZnPP function as antagonists of REV-ERB function...
July 18, 2014: Journal of Biological Chemistry
Elaine Vieira, Laura Marroquí, Ana Lucia C Figueroa, Beatriz Merino, Rebeca Fernandez-Ruiz, Angel Nadal, Thomas P Burris, Ramon Gomis, Ivan Quesada
Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition) in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0...
2013: PloS One
Jürgen A Ripperger, Urs Albrecht
A hallmark of the mammalian circadian timing system is synchronization of physiology and behavior, but when this synchronization is disturbed, chronic diseases such as metabolic syndrome and depression may develop. Three new studies show that nuclear receptors of the Rev-Erb family impact the circadian oscillator and its metabolic output and this can be modified with specific agonists. Hence, resynchronization of metabolic pathways by manipulation of the circadian oscillator using REV-ERB-specific agonists may represent a feasible therapeutic concept to target diseases rooted in a misaligned circadian system...
September 2012: Cell Research
Laura A Solt, Yongjun Wang, Subhashis Banerjee, Travis Hughes, Douglas J Kojetin, Thomas Lundasen, Youseung Shin, Jin Liu, Michael D Cameron, Romain Noel, Seung-Hee Yoo, Joseph S Takahashi, Andrew A Butler, Theodore M Kamenecka, Thomas P Burris
Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice...
March 29, 2012: Nature
Naresh Kumar, Laura A Solt, Yongjun Wang, Pamela M Rogers, Gargi Bhattacharyya, Theodore M Kamenecka, Keith R Stayrook, Christine Crumbley, Z Elizabeth Floyd, Jeffrey M Gimble, Patrick R Griffin, Thomas P Burris
The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbalpha expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis...
July 2010: Endocrinology
Sathiya N Ramakrishnan, Patrick Lau, Lisa M Crowther, Mark E Cleasby, Susan Millard, Gary M Leong, Gregory J Cooney, George E O Muscat
The nuclear hormone receptor, Rev-erb beta operates as a transcriptional silencer. We previously demonstrated that exogenous expression of Rev-erb betaDeltaE in skeletal muscle cells increased Srebp-1c mRNA expression. We validated these in vitro observations by injection of an expression vector driving Rev-erb betaDeltaE expression into mouse tibialis muscle that resulted in increased Srebp-1c mRNA expression. Paradoxically, Rev-erb beta siRNA expression in skeletal muscle cells repressed Srebp-1c expression, and indicated that Rev-erb beta expression was necessary for Srebp-1c expression...
October 30, 2009: Biochemical and Biophysical Research Communications
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