scholarly journals Circadian clock genes and respiratory neuroplasticity genes oscillate in the phrenic motor system

2020 ◽  
Vol 318 (6) ◽  
pp. R1058-R1067
Author(s):  
Mia N. Kelly ◽  
Danelle N. Smith ◽  
Michael D. Sunshine ◽  
Ashley Ross ◽  
Xiping Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Motor Neurons ◽  
Motor System ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Circadian Clock Genes ◽  
Caudal Medulla

Circadian rhythms are endogenous and entrainable daily patterns of physiology and behavior. Molecular mechanisms underlie circadian rhythms, characterized by an ~24-h pattern of gene expression of core clock genes. Although it has long been known that breathing exhibits circadian rhythms, little is known concerning clock gene expression in any element of the neuromuscular system controlling breathing. Furthermore, we know little concerning gene expression necessary for specific respiratory functions, such as phrenic motor plasticity. Thus, we tested the hypotheses that transcripts for clock genes ( Bmal1, Clock, Per1, and Per2) and molecules necessary for phrenic motor plasticity ( Htr2a, Htr2b, Bdnf, and Ntrk2) oscillate in regions critical for phrenic/diaphragm motor function via RT-PCR. Tissues were collected from male Sprague-Dawley rats entrained to a 12-h light-dark cycle at 4 zeitgeber times (ZT; n = 8 rats/group): ZT5, ZT11, ZT17, and ZT23; ZT0 = lights on. Here, we demonstrate that 1) circadian clock genes ( Bmal1, Clock, Per1, and Per2) oscillate in regions critical for phrenic/diaphragm function, including the caudal medulla, ventral C3–C5 cervical spinal cord, and diaphragm; 2) the clock protein BMAL1 is localized within CtB-labeled phrenic motor neurons; 3) genes necessary for intermittent hypoxia-induced phrenic/diaphragm motor plasticity ( Htr2b and Bdnf) oscillate in the caudal medulla and ventral C3–C5 spinal cord; and 4) there is higher intensity of immunofluorescent BDNF protein within phrenic motor neurons at ZT23 compared with ZT11 ( n = 11 rats/group). These results suggest local circadian clocks exist in the phrenic motor system and confirm the potential for local circadian regulation of neuroplasticity and other elements of the neural network controlling breathing.

scholarly journals Modulatory Effects of Circadian Rhythms in the Lung Adenocarcinoma Tumor Microenvironment

2021 ◽  
Author(s):  
Qianzhun Huang ◽  
Xiaoyang Su ◽  
Ning Fang ◽  
Jian Huang
Keyword(s):  
Tumor Microenvironment ◽  
Circadian Rhythms ◽  
Lung Adenocarcinoma ◽  
Circadian Clock ◽  
Drug Sensitivity ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Functional Enrichment ◽  
Expression Levels ◽  
Circadian Clock Genes

Abstract Background: Dysregulated circadian dynamic balance is strongly associated with cancer development. However, biological functions of circadian rhythms in lung adenocarcinoma (LUAD) have not been elucidated. This study aimed at valuating the modulatory effects of circadian rhythms in the LUAD tumor microenvironment.Methods: Multiple open-source bioinformatics research platforms are used to comprehensively elucidate the expression level, prognosis, potential biological function, drug sensitivity, and immune microenvironment of circadian clock genes in LUAD.Results: Most circadian clock genes in LUAD are dysregulated and are strongly correlated with patient prognosis, and missense mutations at splicing sites of these genes. Besides, these genes are closely associated with some well-known cancer-related marker pathways, which are mainly involved in the inhibition of the Apoptosis, Cell cycle, and DNA Damage Response Pathway. Furthermore, functional enrichment analysis revealedthat circadian clock genes regulate transcription factor activities and circadian rhythms in LUAD tissues. As for drug sensitivity, high expression of CLOCK, CRY1, and NR1D2 as well as suppressedPER2 and CRY2 expression levels are associated with drug resistance. The expression levels of circadian clock genes in LUAD correlate with immune infiltration and are involved in the regulation of immunosuppression.Conclusions: Our multi-omics analysis provides a more comprehensive understanding of the molecular mechanisms of the circadian clock genes in LUAD and provides new insights for a more precise screening of prognostic biomarkers and immunotherapy.

scholarly journals Transcriptomal dissection of soybean circadian rhythmicity in two geographically, phenotypically and genetically distinct cultivars

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yanlei Yue ◽  
Ze Jiang ◽  
Enoch Sapey ◽  
Tingting Wu ◽  
Shi Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Chromosome Structure ◽  
Clock Genes ◽  
Expression Profiles ◽  
Circadian Rhythmicity ◽  
Rna Seq ◽  
Night Time ◽  
Time Points ◽  
Circadian Clock Genes

Abstract Background In soybean, some circadian clock genes have been identified as loci for maturity traits. However, the effects of these genes on soybean circadian rhythmicity and their impacts on maturity are unclear. Results We used two geographically, phenotypically and genetically distinct cultivars, conventional juvenile Zhonghuang 24 (with functional J/GmELF3a, a homolog of the circadian clock indispensable component EARLY FLOWERING 3) and long juvenile Huaxia 3 (with dysfunctional j/Gmelf3a) to dissect the soybean circadian clock with time-series transcriptomal RNA-Seq analysis of unifoliate leaves on a day scale. The results showed that several known circadian clock components, including RVE1, GI, LUX and TOC1, phase differently in soybean than in Arabidopsis, demonstrating that the soybean circadian clock is obviously different from the canonical model in Arabidopsis. In contrast to the observation that ELF3 dysfunction results in clock arrhythmia in Arabidopsis, the circadian clock is conserved in soybean regardless of the functional status of J/GmELF3a. Soybean exhibits a circadian rhythmicity in both gene expression and alternative splicing. Genes can be grouped into six clusters, C1-C6, with different expression profiles. Many more genes are grouped into the night clusters (C4-C6) than in the day cluster (C2), showing that night is essential for gene expression and regulation. Moreover, soybean chromosomes are activated with a circadian rhythmicity, indicating that high-order chromosome structure might impact circadian rhythmicity. Interestingly, night time points were clustered in one group, while day time points were separated into two groups, morning and afternoon, demonstrating that morning and afternoon are representative of different environments for soybean growth and development. However, no genes were consistently differentially expressed over different time-points, indicating that it is necessary to perform a circadian rhythmicity analysis to more thoroughly dissect the function of a gene. Moreover, the analysis of the circadian rhythmicity of the GmFT family showed that GmELF3a might phase- and amplitude-modulate the GmFT family to regulate the juvenility and maturity traits of soybean. Conclusions These results and the resultant RNA-seq data should be helpful in understanding the soybean circadian clock and elucidating the connection between the circadian clock and soybean maturity.

Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4613-4613
Author(s):  
Ming-Yu Yang ◽  
Pai-Mei Lin ◽  
Jui-Feng Hsu ◽  
Wen-Chi Yang ◽  
Yi-Chang Liu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Myeloid Leukemia ◽  
Clock Genes ◽  
Expression Patterns ◽  
Healthy Individuals ◽  
Daily Pattern ◽  
Genes Expression ◽  
Circadian Clock Genes

Abstract Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SPF45-related splicing factor for phytochrome signaling promotes photomorphogenesis by regulating pre-mRNA splicing in Arabidopsis

2017 ◽  
Vol 114 (33) ◽  
pp. E7018-E7027 ◽  
Author(s):  
Ruijiao Xin ◽  
Ling Zhu ◽  
Patrice A. Salomé ◽  
Estefania Mancini ◽  
Carine M. Marshall ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Fluorescent Protein ◽  
Clock Genes ◽  
Mrna Processing ◽  
Mrna Splicing ◽  
Splicing Factor ◽  
Light Signaling ◽  
Small Nuclear Ribonucleoprotein

Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human splicing factor 45 (SPF45) named splicing factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FACTORS (PIFs) transcription factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA splicing of light signaling and circadian clock genes.

scholarly journals Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

2020 ◽  
Author(s):  
Yangbo Xiao ◽  
Ye Yuan ◽  
Mariana Jimenez ◽  
Neeraj Soni ◽  
Swathi Yadlapalli
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Nuclear Envelope ◽  
Circadian Clock ◽  
Clock Genes ◽  
Circadian Clocks ◽  
Spatiotemporal Organization ◽  
Clock Proteins ◽  
Expression Behavior ◽  
Clock Protein

ABSTRACTCircadian clocks regulate ∼24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms.SIGNIFICANCEAlmost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate ∼24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.

scholarly journals Differential Expression of Circadian Clock Genes in the Bovine Neuroendocrine Adrenal System

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A66-A67
Author(s):  
Audrey L Earnhardt ◽  
David G Riley ◽  
Noushin Ghaffari ◽  
Penny K Riggs ◽  
Charles R Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Clock Gene ◽  
Target Genes ◽  
Clock Genes ◽  
Expression Profiles ◽  
Primary Objective ◽  
Clock Gene Expression ◽  
Adrenal System ◽  
Circadian Clock Genes

Abstract The primary objective of this investigation was to determine whether circadian clock genes were differentially expressed within or among bovine hypothalamic paraventricular nucleus (PVN), anterior pituitary gland (AP), adrenocortical (AC) and adrenomedullary (AM) tissues. The PVN, AP, AC, and AM were isolated from 5-yr-old Brahman cows (n = 8) harvested humanely at an abattoir between 0800-1100 h. Expression of target genes in each sample was evaluated via RNA-sequencing analyses. Gene counts were normalized using the trimmed mean of M values (TMM) method in the edgeR Package from Bioconductor, R. The normalized gene counts of genes important for circadian rhythm were statistically analyzed using the GLM Procedure of SAS. The genes analyzed were circadian locomotor output cycles protein kaput (CLOCK), cryptochrome circadian regulator 1 and 2 (CRY1 and CRY2), aryl hydrocarbon receptor nuclear translocator like (ARNTL), period circadian regulator 1 and 2 (PER1 and PER2), neuronal PAS domain protein 2 (NPAS2), and nuclear receptor subfamily 1 group D member 1 (NR1D1). Overall, relative expression profiles of clock genes differed (P &lt; 0.01) within each tissue with PER1 having greater expression in all tissues (P &lt; 0.01). Within the PVN expression of CLOCK, CRY1, ARNTL, and PER2 was less than that of CRY2, NPAS2, and NR1D1 (P &lt; 0.01). In the AP, with the exception of PER1, no other clock gene differed in degree of expression. In the AC, expression of CLOCK and NPAS2 was greater than CRY1, ARNTL, PER2, and NR1D1 (P &lt; 0.05), whereas CRY2 expression exceeded only CRY1 (P &lt; 0.05). Within the AM, CLOCK and CRY2 expression was greater than CRY1 and ARNTL (P &lt; 0.05). Overall, clock gene expression among tissues differed (P &lt; 0.01) for each individual clock gene. The AC and AM had similar clock gene expression, except expression of CRY2 and PER2 was greater in AM (P &lt; 0.05). The AC and AM had greater expression of CLOCK than the PVN and AP (P &lt; 0.01), with PVN having greater expression than AP (P &lt; 0.01). The AP had greater expression of NPAS2, followed by PVN, with the least expression in the AC and AM (P &lt; 0.01). Both PVN and AP had greater CRY1 and NR1D1 expression than AC or AM (P &lt; 0.01). The AP had greater PER1 expression than PVN, AC, and AM (P &lt; 0.01), whereas PVN, AC, and AM had greater ARNTL expression than AP (P &lt; 0.05). Both AP and AM had greater expression of PER2 than PVN or AC (P &lt; 0.01). The PVN had greater expression of CRY2 than the AP, AC, and AM (P &lt; 0.01). These results indicated that within each tissue the various clock genes were expressed in different quantities. Also, the clock genes were expressed differentially among the tissues of the bovine neuroendocrine adrenal system. Temporal relationships of these genes with the primary endocrine products of these tissues should be investigated to define the roles of peripheral clock genes in regulation of metabolism and health.

scholarly journals Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

2021 ◽  
Vol 118 (28) ◽  
pp. e2019756118
Author(s):  
Yangbo Xiao ◽  
Ye Yuan ◽  
Mariana Jimenez ◽  
Neeraj Soni ◽  
Swathi Yadlapalli
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Nuclear Envelope ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Nuclear Periphery ◽  
Spatiotemporal Organization ◽  
Subnuclear Localization ◽  
Clock Proteins ◽  
Spatial Reorganization

Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.

scholarly journals Comparative physiological and transcriptomic analysis of pear leaves under distinct training systems

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zheng Liu ◽  
Liyuan An ◽  
Shihua Lin ◽  
Tao Wu ◽  
Xianming Li ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Light Availability ◽  
Photosynthetic Performance ◽  
Canopy Architecture ◽  
Training Systems ◽  
Carbohydrate Derivative ◽  
Circadian Clock Genes ◽  
Architectural Traits

Abstract Canopy architecture is critical in determining the light interception and distribution, and subsequently the photosynthetic efficiency and productivity. However, the physiological responses and molecular mechanisms by which pear canopy architectural traits impact on photosynthesis remain poorly understood. Here, physiological investigations coupled with comparative transcriptomic analyses were performed in pear leaves under distinct training systems. Compared with traditional freestanding system, flat-type trellis system (DP) showed higher net photosynthetic rate (PN) levels at the most time points throughout the entire monitored period, especially for the interior of the canopy in sunny side. Gene ontology analysis revealed that photosynthesis, carbohydrate derivative catabolic process and fatty acid metabolic process were over-represented in leaves of DP system with open-canopy characteristics. Weighted gene co-expression network analysis uncovered a significant network module positive correlated with PN value. The hub genes (PpFKF1 and PpPRR5) of the module were enriched in circadian rhythm pathway, suggesting a functional role for circadian clock genes in mediating photosynthetic performance under distinct training systems. These results draw a link between pear photosynthetic response and specific canopy architectural traits, and highlight light harvesting and circadian clock network as potential targets for the input signals from the fluctuating light availability under distinct training systems.

scholarly journals Machine Learning and In-Vivo Expression Analyses Reveal Circadian Clock Features Predictive of Anxiety in Humans

2021 ◽  
Author(s):  
Aziz Zafar ◽  
Rebeccah Overton ◽  
Ziad Attia ◽  
Ahmet Ay ◽  
Krista Ingram
Keyword(s):  
Machine Learning ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Clock Gene ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Anxiety Symptoms ◽  
Circadian Phase ◽  
Functional Studies

Abstract Mood disorders, including anxiety, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes. Molecular mechanisms underlying these connections may be direct—via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect—via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3B-AG/CRY1-CG genotype being the strongest predictor of anxiety risk in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3B effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

scholarly journals Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3348 ◽  
Author(s):  
Wen-Kai Li ◽  
Huan Li ◽  
Yuan-Fu Lu ◽  
Ying-Ying Li ◽  
Zidong Donna Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Circadian Clock ◽  
Acid Metabolism ◽  
Clock Genes ◽  
Repeated Administration ◽  
Synthesis Rate ◽  
Bile Acid Metabolism ◽  
High Dose ◽  
Circadian Clock Genes

Aim Atorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia. Atorvastatin is generally safe but may induce cholestasis. The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice. Methods Adult male mice were given atorvastatin (10, 30, and 100 mg/kg, po) daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined. Results Repeated administration of atorvastatin did not affect animal body weight gain or liver weights. Serum enzyme activities were in the normal range. Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1. Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP. In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ. The most dramatic change was the 30-fold induction of Cyp7a1. Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression. Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression. Conclusion Repeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes.

Sign in / Sign up

Export Citation Format

Share Document