Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice

2021 ◽  
pp. 114905
Author(s):  
Josef Skoda ◽  
Klara Dohnalova ◽  
Karel Chalupsky ◽  
Aaron Stahl ◽  
Markus Templin ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Constitutive Androstane Receptor ◽  
Humanized Mice ◽  
Receptor Ligand

scholarly journals Widespread Epigenetic Changes to the Enhancer Landscape of Mouse Liver Induced by a Specific Xenobiotic Agonist Ligand of the Nuclear Receptor CAR

2019 ◽  
Vol 171 (2) ◽  
pp. 315-338 ◽  
Author(s):  
Andy Rampersaud ◽  
Nicholas J Lodato ◽  
Aram Shin ◽  
David J Waxman
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Mouse Liver ◽  
Target Genes ◽  
Constitutive Androstane Receptor ◽  
Chromatin Accessibility ◽  
Epigenetic Changes ◽  
Transcriptional Responses ◽  
Environmental Chemical ◽  
Hypersensitive Sites

AbstractConstitutive androstane receptor (CAR) (Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid, and lipid metabolism and dysregulates genes linked to hepatocellular carcinogenesis, but its impact on the liver epigenome is poorly understood. TCPOBOP (1, 4-bis-[2-(3, 5-dichloropyridyloxy)]benzene), a halogenated xenochemical and highly specific CAR agonist ligand, induces localized chromatin opening or closing at several thousand mouse liver genomic regions, discovered as differential DNase-hypersensitive sites (ΔDHS). Active enhancer and promoter histone marks induced by TCPOBOP were enriched at opening DHS and TCPOBOP-inducible genes. Enrichment of CAR binding and CAR motifs was seen at opening DHS and their inducible drug/lipid metabolism gene targets, and at many constitutively open DHS located nearby. TCPOBOP-responsive cell cycle and DNA replication genes codependent on MET/EGFR signaling for induction were also enriched for CAR binding. A subset of opening DHS and many closing DHS mapping to TCPOBOP-responsive target genes did not bind CAR, indicating an indirect mechanism for their changes in chromatin accessibility. TCPOBOP-responsive DHS were also enriched for induced binding of RXRA, CEBPA, and CEBPB, and for motifs for liver-enriched factors that may contribute to liver-specific transcriptional responses to TCPOBOP exposure. These studies elucidate the enhancer landscape of TCPOBOP-exposed liver and the widespread epigenetic changes that are induced by both direct and indirect mechanisms linked to CAR activation. The global maps of thousands of environmental chemical-induced epigenetic changes described here constitute a rich resource for further research on xenochemical effects on liver chromatin states and the epigenome.

The Role of Xenobiotic Receptors on Hepatic Glycolipid Metabolism

2019 ◽  
Vol 20 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Ke Chen ◽  
Jinwei Zhong ◽  
Lin Hu ◽  
Ruliu Li ◽  
Qun Du ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Energy Metabolism ◽  
Constitutive Androstane Receptor ◽  
Main Idea ◽  
Pregnane X Receptor ◽  
Research Literature ◽  
Negative Regulator ◽  
Glucose And Lipid Metabolism ◽  
Obesity And Diabetes ◽  
Hepatic Glucose

Background: PXR (Pregnane X Receptor) and CAR (Constitutive Androstane Receptor) are termed as xenobiotic receptors, which are known as core factors in regulation of the transcription of metabolic enzymes and drug transporters. However, accumulating evidence has shown that PXR and CAR exert their effects on energy metabolism through the regulation of gluconeogenesis, lipogenesis and β-oxidation. Therefore, in this review, we are trying to summary recent advances to show how xenobiotic receptors regulate energy metabolism. Methods: A structured search of databases has been performed by using focused review topics. According to conceptual framework, the main idea of research literature was summarized and presented. Results: For introduction of each receptor, the general introduction and the critical functions in hepatic glucose and lipid metabolism have been included. Recent important studies have shown that CAR acts as a negative regulator of lipogenesis, gluconeogenesis and β -oxidation. PXR activation induces lipogenesis, inhibits gluconeogenesis and inhabits β-oxidation. Conclusion: In this review, the importance of xenobiotic receptors in hepatic glucose and lipid metabolism has been confirmed. Therefore, PXR and CAR may become new therapeutic targets for metabolic syndrome, including obesity and diabetes. However, further research is required to promote the clinical application of this new energy metabolism function of xenobiotic receptors.

scholarly journals Diazepam Promotes Translocation of Human Constitutive Androstane Receptor (CAR) via Direct Interaction with the Ligand-Binding Domain

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2532
Author(s):  
Josef Skoda ◽  
Jan Dusek ◽  
Martin Drastik ◽  
Alzbeta Stefela ◽  
Klara Dohnalova ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Constitutive Androstane Receptor ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Humanized Mice ◽  
Luciferase Reporter ◽  
Heparg Cells ◽  
Reporter Assays

The constitutive androstane receptor (CAR) is the essential regulator of genes involved both in xenobiotic and endobiotic metabolism. Diazepam has been shown as a potent stimulator of CAR nuclear translocation and is assumed as an indirect CAR activator not interacting with the CAR cavity. In this study, we sought to determine if diazepam is a ligand directly interacting with the CAR ligand binding domain (LBD) and if it regulates its target genes in a therapeutically relevant concentration. We used different CAR constructs in translocation and luciferase reporter assays, recombinant CAR-LBD in a TR-FRET assay, and target genes induction studied in primary human hepatocytes (PHHs), HepaRG cells, and in CAR humanized mice. We also used in silico docking and CAR-LBD mutants to characterize the interaction of diazepam and its metabolites with the CAR cavity. Diazepam and its metabolites such as nordazepam, temazepam, and oxazepam are activators of CAR+Ala in translocation and two-hybrid assays and fit the CAR cavity in docking experiments. In gene reporter assays with CAR3 and in the TR-FRET assay, only diazepam significantly interacts with CAR-LBD. Diazepam also promotes up-regulation of CYP2B6 in PHHs and in HepaRG cells. However, in humanized CAR mice, diazepam significantly induces neither CYP2B6 nor Cyp2b10 genes nor does it regulate critical genes involved in glucose and lipids metabolism and liver proliferation. Thus, we demonstrate that diazepam interacts with human CAR-LBD as a weak ligand, but it does not significantly affect expression of tested CAR target genes in CAR humanized mice.

A Cytochemical Study of Glucose-6-Phosphatase (G-6-PASE) in Cells Participating in Atherogenesis of Rabbit Aorta

1975 ◽  
Vol 33 ◽  
pp. 460-461
Author(s):  
Sidney D. Kobernick ◽  
Edna A. Elfont ◽  
Neddra L. Brooks
Keyword(s):  
Lipid Metabolism ◽  
New Zealand ◽  
Aortic Wall ◽  
Rabbit Aorta ◽  
Plaque Formation ◽  
Metabolic Changes ◽  
Atherosclerotic Plaques ◽  
Cytochemical Study ◽  
Cellular Alteration ◽  
New Zealand White Rabbits

This cytochemical study was designed to investigate early metabolic changes in the aortic wall that might lead to or accompany development of atherosclerotic plaques in rabbits. The hypothesis that the primary cellular alteration leading to plaque formation might be due to changes in either carbohydrate or lipid metabolism led to histochemical studies that showed elevation of G-6-Pase in atherosclerotic plaques of rabbit aorta. This observation initiated the present investigation to determine how early in plaque formation and in which cells this change could be observed.Male New Zealand white rabbits of approximately 2000 kg consumed normal diets or diets containing 0.25 or 1.0 gm of cholesterol per day for 10, 50 and 90 days. Aortas were injected jin situ with glutaraldehyde fixative and dissected out. The plaques were identified, isolated, minced and fixed for not more than 10 minutes. Incubation and postfixation proceeded as described by Leskes and co-workers.

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