Orchestration of gene expression and physiology by the circadian clock

Albrecht, Urs

doi:10.1016/j.jphysparis.2007.05.004

Cited by 27 publications

(19 citation statements)

References 97 publications

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“…In mammals, many physiological and behavioral processes exhibit daily oscillations, including many hepatic enzyme activities, including those involved in energy metabolism, and a clear link between the control of circadian rhythm and metabolism has been established (Albrecht, 2006;Hastings et al, 2007). The clock oscillator consists of interlocked positive and negative transcriptional/posttranscriptional feedback loops between the clock genes Clock/Bmal1 and Per/Crys.…”

Section: Discussionmentioning

confidence: 99%

Identification of HumanCYP2C8as a Retinoid-Related Orphan Nuclear Receptor Target Gene

Chen

Coulter²,

Jetten³

et al. 2009

J Pharmacol Exp Ther

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Retinoid-related orphan nuclear receptors (RORs) ␣ and ␥ (NR1F1, -3) are highly expressed in liver, adipose tissue, thymus, and brain and are involved in many physiological processes, such as circadian rhythm and immune function. Enzymes in the cytochrome P450 2C subfamily metabolize many clinically important drugs and endogenous compounds, such as the anticancer drug paclitaxel and arachidonic acid, and are highly expressed in liver. Here, we present the first evidence that RORs regulate the transcription of human CYP2C8. Overexpression of ROR␣ and ROR␥ in HepG2 cells significantly enhanced the activity of the CYP2C8 promoter but not that of the CYP2C9 or CYP2C19 promoters. Computer analyses, promoter deletion studies, gel shift assays, and mutational analysis identified an essential ROR-responsive element at Ϫ2045 base pairs in the CYP2C8 promoter that mediates ROR transactivation. Adenoviral overexpression of ROR␣ and -␥ significantly induced endogenous CYP2C8 transcripts in both HepG2 cells and human primary hepatocytes. Knockdown of endogenous ROR␣ and -␥ expression in HepG2 cells by RNA interference decreased the expression of endogenous CYP2C8 mRNA by ϳ50%. These data indicate that RORs transcriptionally upregulate CYP2C8 in human liver and, therefore, may be important modulators of the metabolism of drugs and physiologically active endogenous compounds by this enzyme in liver and possibly extrahepatic tissues where RORs are expressed.The human CYP2C subfamily consists of four genes: CYP2C8, CYP2C9, CYP2C18, and CYP2C19. CYP2C18 does not seem to be expressed at the protein level. The other three CYP2C enzymes metabolize approximately 20% of currently used clinical drugs, including the antidiabetic drugs tolbutamide and rosiglitazone, the anticoagulant drug warfarin, the anticonvulsant phenytoin, the antiulcer drug omeprazole, the anticancer drug paclitaxel, and numerous nonsteroidal antiinflammatory drugs, such as ibuprofen (Goldstein, 2001). They are also involved in the oxidative metabolism of endogenous compounds, such as arachidonic acid and retinoic acid.It is well known that there is marked variability in the metabolism of CYP2C substrates in human populations because of the occurrence of genetic polymorphisms in the CYP2C genes. The expression of CYP2C enzymes also has been reported to be induced by various drugs, including rifampicin, hyperforin (the active constituent in St. John's Wort), phenobarbital, and dexamethasone (Raucy et al., 2002;Madan et al., 2003;Komoroski et al., 2004). This induction further amplifies the individual variability in drug metabolism in human populations and may lead to a change in the half-life of drugs and then eventually result in drug tolerance or therapeutic failure.A number of nuclear receptors have been discovered to play important roles in the mediation of transactivation of P450 enzymes. In many cases, these nuclear receptors bind ligands, which may be involved in initiating translocation of the receptor to the nucleus, where the receptor binds to resp...

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Section: Discussionmentioning

confidence: 99%

Identification of HumanCYP2C8as a Retinoid-Related Orphan Nuclear Receptor Target Gene

Chen

Coulter²,

Jetten³

et al. 2009

J Pharmacol Exp Ther

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“…While circadian rhythmicity driven by clock gene expression can be seen in both the SCN and in tissues throughout the brain and body, only the rhythms in the SCN are self-sustaining. This master pacemaker thus sits atop a hierarchy where it orchestrates the circadian organization of multiple physiological systems below (Albrecht, 2006; Liu et al, 2007; Yamazaki et al, 2000). The circadian timing system has proven relevant to a wide array of health conditions (Maywood et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Ethanol consumption in mice: relationships with circadian period and entrainment

Trujillo

David

Grahame

et al. 2011

Alcohol

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A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep and body temperature, and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred High- (HAP) and Low- (LAP) Alcohol Preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 h or 22 h or remained in a standard 24 h cycle. Upon discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake.

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“…Regulation of Clock Genes Anexcellent exampleofabiologicalfeedbacksystem, which is also subject to environmental modifications, is the molecular system of the biological clock thathas beenstudied extensively (Ueda,2007).Transcription ofthe per(period)and other genes of this system is high when the concentrations of the respective proteins are low (Albrecht, 2006). This results in translation of increasingly more protein that enters the nucleus and represses its own gene transcription or transcription of other clock genes (Hirayama and Sassone-Corsi, 2005).…”

Section: Gene Regulation -Circular Signaling Pathwaysmentioning

confidence: 99%