LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver

2013 ◽  
Vol 52 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Feng Wang ◽  
Xianfeng Zhang ◽  
Jiqiu Wang ◽  
Maopei Chen ◽  
Nengguang Fan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Clock Genes ◽  
Plasma Cholesterol ◽  
Plasma Lipid ◽  
Microsomal Triglyceride Transfer Protein ◽  
Underlying Mechanism ◽  
Transcriptional Level ◽  
Cholesterol Levels

The circadian clock plays an important role in the liver by regulating the major aspects of energy metabolism. Currently, it is assumed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level, but the underlying mechanism is not well understood. In this study, we showed that Lgr4 homozygous mutant (Lgr4m/m) mice showed alteration in the rhythms of the respiratory exchange ratio. We further detected impaired plasma triglyceride rhythms in Lgr4m/m mice. Although no significant changes in plasma cholesterol rhythms were observed in the Lgr4m/m mice, their cholesterol levels were obviously lower. This phenotype was further confirmed in the context of ob/ob mice, in which lack of LGR4 dampened circadian rhythms of triglyceride. We next demonstrated that Lgr4 expression exhibited circadian rhythms in the liver tissue and primary hepatocytes in mice, but we did not detect changes in the expression levels or circadian rhythms of classic clock genes, such as Clock, Bmal1 (Arntl), Pers, Rev-erbs, and Crys, in Lgr4m/m mice compared with their littermates. Among the genes related to the lipid metabolism, we found that the diurnal expression pattern of the Mttp gene, which plays an important role in the regulation of plasma lipid levels, was impaired in Lgr4m/m mice and primary Lgr4m/m hepatocytes. Taken together, our results demonstrate that LGR4 plays an important role in the regulation of plasma lipid rhythms, partially through regulating the expression of microsomal triglyceride transfer protein. These data provide a possible link between the peripheral circadian clock and lipid metabolism.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

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 Effect of Basil Seed and Chia SeedExtracts on Blood Lipid Profile

2021 ◽  
Vol 15 (6) ◽  
pp. 1368-1371
Author(s):  
S. Munir ◽  
S. Khurshid ◽  
Q. J. Iqbal ◽  
N. Iqbal ◽  
Z. Masood
Keyword(s):  
Body Weight ◽  
Lipid Profile ◽  
Plasma Cholesterol ◽  
Plasma Lipid ◽  
Blood Lipid ◽  
Histopathological Analysis ◽  
Omega 3 ◽  
Blood Lipid Profile ◽  
Cholesterol Levels ◽  
Maintain Body Weight

Background: Basil and Chia seeds contain higher nutritive values like vitamin, carbohydrates, Omega-3 oil and other dietary fibers. With all these rich dietary benefits these seeds regulate necessary health conditions and maintain body weight. Ocimumbasilicum (Basil) plant have been known to contain properties of weight loss, better digestion and other health benefits. Aim: To check the Basil seed against hyperlipidemia in mice with Chia seeds. Methodology: In this research, the effect of both seeds extract on body weight and plasma lipid profile were estimated in Albino mice after raising their cholesterol levels by high fatty diet. The experiments were performed in different groups like normal control, standard control, hyperlipidemia group and four groups of diet supplemented chia or basil seeds with two different doses. Results: The biochemical analysis revealed that the supplementation of Basil seeds (400mg/kg/day) significantly lowered the levels of total plasma cholesterol, lipoproteins and triacylglycerol. Moreover, histopathological analysis of vital organs like kidneys, heart reported no toxicity. Conclusion: Extracts of Chia and Basil seeds have shown controlling effects over the given parameters in the blood and weights of the animals and these may have potential to control high fat diet-induced hyperlipidemia when taken as dietary supplements. Keywords: Cholesterol, Hyperlipidemia, Ocimumbasilicum, Salvia hispanica

scholarly journals Modeling and analysis of the impacts of jet lag on circadian rhythm and its role in tumor growth

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4877 ◽  
Author(s):  
Azka Hassan ◽  
Jamil Ahmad ◽  
Hufsah Ashraf ◽  
Amjad Ali
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Clock Genes ◽  
Damage Control ◽  
Vital Role ◽  
Biochemical Networks ◽  
Jet Lag ◽  
Peripheral Tissues ◽  
Modeling And Analysis ◽  
Circadian Clock Proteins

Circadian rhythms maintain a 24 h oscillation pattern in metabolic, physiological and behavioral processes in all living organisms. Circadian rhythms are organized as biochemical networks located in hypothalamus and peripheral tissues. Rhythmicity in the expression of circadian clock genes plays a vital role in regulating the process of cell division and DNA damage control. The oncogenic protein, MYC and the tumor suppressor, p53 are directly influenced by the circadian clock. Jet lag and altered sleep/wake schedules prominently affect the expression of molecular clock genes. This study is focused on developing a Petri net model to analyze the impacts of long term jet lag on the circadian clock and its probable role in tumor progression. The results depict that jet lag disrupts the normal rhythmic behavior and expression of the circadian clock proteins. This disruption leads to persistent expression of MYC and suppressed expression of p53. Thus, it is inferred that jet lag altered circadian clock negatively affects the expressions of cell cycle regulatory genes and contribute in uncontrolled proliferation of tumor cells.

Dietary Protein Source and Plasma Lipid Profiles of Infants

PEDIATRICS ◽  
1990 ◽  
Vol 85 (4) ◽  
pp. 548-552
Author(s):  
Emily Tseng ◽  
Susan M. Potter ◽  
Mary Frances Picciano
Keyword(s):  
Amino Acids ◽  
Human Milk ◽  
Dietary Protein ◽  
Plasma Cholesterol ◽  
Plasma Lipid ◽  
Lipid Profiles ◽  
Plasma Triglyceride ◽  
Term Infants ◽  
Cholesterol Levels ◽  
The Impact

Total cholesterol and triglyceride concentrations were measured in plasma samples taken at 4 and 8 weeks of age from 40 full-term infants who had been fed either human milk or one of three formulas containing casein-to-whey ratios of 82:18, 66:34, or 50:50 to investigate whether dietary protein influenced the development of plasma lipid profiles. Infants fed the formula with the casein-to-whey ratio of 82:18 had significantly higher plasma cholesterol levels at both 4 and 8 weeks of age compared with other groups of infants (P < .05). Infants fed the high-casein formula also showed an increase in plasma cholesterol levels with time (P < .001). Plasma triglyceride concentrations decreased as concentration of casein decreased (P < .05) among the formula-fed groups and increased with time. Infants fed human milk had plasma triglyceride concentrations similar to those infants who had been fed the 82:18 formula at 4 weeks of age; however, triglyceride concentrations eventually fell and were similar to those concentrations in infants who had been fed the 50:50 formula at 8 weeks of age. Results indicate that constituent lipids of human milk or formulas were not determining factors for changes observed in plasma cholesterol levels and triglyceride concentrations among groups. Since formulas differed only in proteins and their constituent amino acids, further investigation of the impact of dietary protein (amino acids) on development of blood lipid profiles in infants is warranted.

scholarly journals Administration of Exogenous Melatonin Improves the Diurnal Rhythms of the Gut Microbiota in Mice Fed a High-Fat Diet

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Jie Yin ◽  
Yuying Li ◽  
Hui Han ◽  
Jie Ma ◽  
Gang Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Circadian Clock ◽  
High Fat Diet ◽  
Serum Lipid ◽  
Clock Genes ◽  
Diurnal Rhythms ◽  
High Fat ◽  
Exogenous Melatonin ◽  
Circadian Clock Genes

ABSTRACT Melatonin, a circadian hormone, has been reported to improve host lipid metabolism by reprogramming the gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of the administration of exogenous melatonin on the diurnal variation in the gut microbiota in mice fed a high-fat diet (HFD) is unclear. Here, we further confirmed the antiobesogenic effect of melatonin on mice fed an HFD for 2 weeks. Samples were collected every 4 h within a 24-h period, and diurnal rhythms of clock gene expression (Clock, Cry1, Cry2, Per1, and Per2) and serum lipid indexes varied with diurnal time. Notably, Clock and triglycerides (TG) showed a marked rhythm in the control in melatonin-treated mice but not in the HFD-fed mice. The rhythmicity of these parameters was similar between the control and melatonin-treated HFD-fed mice compared with that in the HFD group, indicating an improvement caused by melatonin in the diurnal clock of host metabolism in HFD-fed mice. Moreover, 16S rRNA gene sequencing showed that most microbes exhibited daily rhythmicity, and the trends were different for different groups and at different time points. We also identified several specific microbes that correlated with the circadian clock genes and serum lipid indexes, which might indicate the potential mechanism of action of melatonin in HFD-fed mice. In addition, effects of melatonin exposure during daytime or nighttime were compared, but a nonsignificant difference was noticed in response to HFD-induced lipid dysmetabolism. Interestingly, the responses of microbiota-transplanted mice to HFD feeding also varied at different transplantation times (8:00 and 16:00) and with different microbiota donors. In summary, the daily oscillations in the expression of circadian clock genes, serum lipid indexes, and the gut microbiota appeared to be driven by short-term feeding of an HFD, while administration of exogenous melatonin improved the composition and diurnal rhythmicity of some specific gut microbiota in HFD-fed mice. IMPORTANCE The gut microbiota is strongly shaped by a high-fat diet, and obese humans and animals are characterized by low gut microbial diversity and impaired gut microbiota compositions. Comprehensive data on mammalian gut metagenomes shows gut microbiota exhibit circadian rhythms, which is disturbed by a high-fat diet. On the other hand, melatonin is a natural and ubiquitous molecule showing multiple mechanisms of regulating the circadian clock and lipid metabolism, while the role of melatonin in the regulation of the diurnal patterns of gut microbial structure and function in obese animals is not yet known. This study delineates an intricate picture of melatonin-gut microbiota circadian rhythms and may provide insight for obesity intervention.

scholarly journals JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Improves Hyperglycemia and Dyslipidemia Independent of Suppression of Food Intake in Diabetic Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Shohei Sakata ◽  
Makoto Ito ◽  
Yasuko Mera ◽  
Tomohiko Sasase ◽  
Hiromi Yamamoto ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Treatment Group ◽  
Food Intake ◽  
Plasma Cholesterol ◽  
Specific Inhibitor ◽  
Microsomal Triglyceride Transfer Protein ◽  
Diabetic Rats ◽  
Glucose And Lipid Metabolism ◽  
Zdf Rats ◽  
Glucagon Like Peptide 1

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group.Results. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment.Conclusions. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.

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 Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock

2021 ◽  
Vol 15 ◽  
Author(s):  
Daisuke Ono ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cellular Networks ◽  
Clock Genes ◽  
Circadian System ◽  
Developmental Changes ◽  
Circadian Period ◽  
Functional Roles ◽  
Environmental Light

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in the SCN. Several neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) are expressed in the SCN, where these neuropeptides function as synchronizers and are important for entrainment to environmental light and for determining the circadian period. These neuropeptides are also related to developmental changes of the circadian system of the SCN. Transcription factors are required for the formation of neuropeptide-related neuronal networks. Although VIP is critical for synchrony of circadian rhythms in the neonatal SCN, it is not required for synchrony in the embryonic SCN. During postnatal development, the clock genes cryptochrome (Cry)1 and Cry2 are involved in the maturation of cellular networks, and AVP is involved in SCN networks. This mini-review focuses on the functional roles of neuropeptides in the SCN based on recent findings in the literature.

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.

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