Biliary excretion of excess iron in mice
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Thomas Bartnikas
PROVIDER: MSV000086836 | MassIVE | Wed Feb 10 11:59:00 GMT 2021
REPOSITORIES: MassIVE
Similar Datasets
Project description:Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of these pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4-weeks treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile-derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a fourfold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.
2016-11-04 | GSE77236 | GEO
Project description:ABSTRACT Background & aims: The role of the intestine in the maintenance of cholesterol homeostasis is increasingly recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport (RCT) pathway, to which both biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway are,however, poorly understood. In the current study we aimed to identify treatment modalities that stimulate TICE and to uncover underlying driving mechanisms. Methods: TICE was assessed in a panel of knock-out and transgenic mice as well as in mice treated with the FXR agonist PX20606 either or not combined with the cholesterol absorption inhibitor ezetimibe. Results: We show that TICE is regulated by intestinal farnesoid X receptor (FXR) via its target fibroblast growth factor 15/19 (FGF15/19) and that the pathway can be stimulated to such an extent that mice excrete ~60% of their total cholesterol content each day. Both PX20606 and FGF19 increased the muricholate/cholate ratio in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool robustly stimulated secretion of cholesterol into the intestinal lumen via the sterol exporting heterodimer ATP binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, we demonstrate that the increase in TICE induced by PX20206 is independent of changes in cholesterol absorption. Conclusions: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Translation of these results to humans may offer new treatment modalities for prevention of cardiovascular disease.
2017-01-10 | GSE74101 | GEO
Project description:The Th2 cytokine IL-13 has been described to be involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. IL-13 was found to reduce tight junction-associated barrier function of bile ducts, to promote cholangiocyte hyperplasia, and thus causing biliary epithelial injury. We generated Abcb4-/-- and IL-13-/- double-knockout mice on fibrosis susceptible genetic background BALB/c. Molecular and cellular mechanisms of hepatic and ileal pathology were investigated by mRNA microarray. Depletion of IL-13 in Abcb4-/--mice resulted in a tenfold decrease of total serum bile acid concentrations at the age of 8 weeks and lead to a recovery of intrahepatic bile duct integrity. The decrease of serum bile acid in 8 week old mice went along with relative enhancement of bile acid excretion and normalization of the composition of fecal bile excretion, correction of fecal microbiome, and improved ileal integrity. Liver integrity, measured by serum ALT, was ameliorated in younger mice and strongly correlated with the concentration of serum bile acids. 52 weeks old Abcb4-/-IL-13-/--mice exhibited significantly reduced hepatic fibrosis.
2020-11-02 | GSE90995 | GEO
Project description:Intake and absorption of cholesterol (the latter determined by double labeled cholesterol methodology) were nearly unchanged in mice fed the saturated fat diet, but the fecal excretion of neutral sterols (i.e. cholesterol and its microbial conversion products) was increased compared with control diet(+80%; p<0.01). The saturated fat diet did neither significantly affect biliary cholesterol secretion nor intestinal cholesterol absorption (49% vs. 65% in controls, double labeled water methodology, p>0.1). Thus, the increased fecal neutral sterol excretion was primarily due to increased net transintestinal cholesterol excretion (+89% versus control; p<0.05). Since a major fraction of TICE cholesterol absorption is normally reabsorbed (J Lipid Res 2019 Sep;60(9):1562-1572), the increased fecal cholesterol excretion could be due to more transintestinal excretion of cholesterol into the intestinal lumen and/or to its decreased reabsorption. The saturated fat diet increased jejunal expression of genes involved in cholesterol synthesis (Srebf2 and target genes), but did not affect whole body de novo cholesterol synthesis. Conclusion This proof-of-principle study shows that increasing the saturation of the dietary fat can stimulate fecal cholesterol excretion. Individual components of saturated fat diets are to be explored to address the responsible molecular mechanisms
2021-02-01 | GSE37097 | GEO
Project description:This the model from the article without the time delays:
A Delayed Nonlinear PBPK Model for Genistein Dosimetry in Rats.
Zager MG, Schlosser PM, Tran HT. Bull Math Biol.
2007 Jan;69(1):93-117. Pubmed ID: 17024552
,
doi: 0.1007/s11538-006-9068-x
.
Abstract:
Genistein is an endocrine-active compound (EAC) found in soy products. It has been linked to beneficial effects such as mammary tumor growth suppression and adverse endocrine-related effects such as reduced birth weight in rats and humans. In its conjugated form, genistein is excreted in the bile, which is a significant factor in its pharmacokinetics. Experimental data suggest that genistein induces a concentration-dependent suppression of biliary excretion. In this article, we describe a physiologically based pharmacokinetic (PBPK) model that focuses on biliary excretion with the goal of accurately simulating the observed suppression. The mathematical model is a system of nonlinear differential equations with state-dependent delay to describe biliary excretion. The model was analyzed to examine local existence and uniqueness of a solution to the equations. Furthermore, unknown parameters were estimated, and the mathematical model was compared against published experimental data.
This model was taken from the CellML repository
and automatically converted to SBML.
Both the CellML version and the converted SBML version do not contain the time dalays of the original model.
The original model was:
Zager, Schlosser, Tran, 2007 version03
The original CellML model was created and curated by:
Lloyd, Catherine, May
c.lloyd(at)auckland.ac.nz
The University of Auckland, Bioengineering Institute
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL6963432821 | BioModels
Project description:Because iron is essential for a healthy pregnancy, iron supplementation during pregnancy is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and so may overestimate iron stores during inflammation or infection. We used mouse models to determine whether maternal iron loading, inflammation, or their interaction caused poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, caused embryo malformations and demise. Maternal iron excess potentiated embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction was dependent on TNFα signaling, caused apoptosis of the placental and embryo endothelium, and was prevented by anti-TNFα or antioxidant treatment in vivo. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.
2021-05-17 | GSE153528 | GEO
Project description:As a key vector for the major arthropod-borne viruses (arboviruses), such as dengue, Zika and chikungunya, control of Aedes aegypti represents a major challenge in public health. Bloodmeal acquisition is necessary for the reproduction of vector mosquitoes and pathogen transmission. Blood contains potentially toxic amounts of iron while it provides nutrients for mosquito offspring; disruption of iron homeostasis in the mosquito may therefore lead to a novel control strategies. We previously described a potential iron exporter in Ae. aegypti after a targeted functional screen of ZIP and ZnT family genes. In this study, we performed an RNAseq-based screen in an Ae. aegypti cell line cultured under iron-deficient and iron-excess conditions. A subset of differentially expressed genes were analyzed via a cytosolic iron-sensitive dual-luciferase reporter assay with several gene candidates potentially involved in iron transport. In vivo gene silencing resulted in significant reduction of fecundity (egg number) and fertility (hatch rate) for one gene, AAEL000471. Consistent with a role in iron homeostasis, ferritin expression in the midgut was reduced upon silencing of AAEL000471. Silencing of AAEL000471 also resulted in delayed/impaired excretion and digestion. Together these studies increase our understanding of gene regulatory networks controlling iron homeostasis in bloodfeeding mosquitoes, and suggest new targets for vector control based on the disruption of this critical process.
2021-04-01 | GSE160498 | GEO
Project description:Bile acids play multiple roles in vertebrate metabolism by facilitating lipid absorption in the intestine and acting as a signaling molecule in lipid and carbohydrate metabolism. Bile acids are also the main route to excrete excess cholesterol out of the body. Alpha-methyl-Coa racemase (Amacr) is one of the enzymes needed to produce bile acids from cholesterol. The mouse model lacking Amacr can produce only minor (less than 10%) amounts of bile acids, but still they are symptomless in normal laboratory conditions. Cholesterol absorption occurs in the jejunum part of the intestine. In this experiment, the intestines from Amacr-/- and wild-type mice were divided into four equal segments and the endothelial layer was collected by scraping. The RNA from these samples was isolated and the gene expression levels in each segment were compared. 3 biological replicates per genotype/segment combination.
2015-12-22 | E-GEOD-40124 | biostudies-arrayexpress
Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease. Eight week old Mig-6f/f vs Mig-6d/d male mice after undergoing a 24 hour fast
2011-08-30 | E-GEOD-31752 | biostudies-arrayexpress
Project description:Bile acids play multiple roles in vertebrate metabolism by facilitating lipid absorption in the intestine and acting as a signaling molecule in lipid and carbohydrate metabolism. Bile acids are also the main route to excrete excess cholesterol out of the body. Alpha-methyl-Coa racemase (Amacr) is one of the enzymes needed to produce bile acids from cholesterol. The mouse model lacking Amacr can produce only minor (less than 10%) amounts of bile acids, but still they are symptomless in normal laboratory conditions. Bile acid synthesis occurs in liver. In this experiment, liver samples from Amacr-/- and wild-type mice were collected and their gene expression levels were compared. 4 biological replicates per genotype.
2015-12-22 | E-GEOD-40085 | biostudies-arrayexpress