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Article ; Online: FXR signaling in the enterohepatic system.

Matsubara, Tsutomu / Li, Fei / Gonzalez, Frank J

2012 Volume 368, Issue 1-2, Page(s) 17–29

Abstract: ... levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and ... farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G ... Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and ...

Abstract	Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism.
MeSH term(s)	Animals ; Bile Acids and Salts/metabolism ; Biological Transport ; Homeostasis ; Humans ; Intestine, Small/metabolism ; Ligands ; Liver/metabolism ; Neoplasms/metabolism ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction ; Xenobiotics/metabolism
Chemical Substances	Bile Acids and Salts ; Ligands ; Receptors, Cytoplasmic and Nuclear ; Xenobiotics ; farnesoid X-activated receptor (0C5V0MRU6P)
Language	English
Publishing date	2012-05-17
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2012.05.004
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Article: FXR signaling in the enterohepatic system

Matsubara, Tsutomu / Li, Fei / Gonzalez, Frank J

Molecular and cellular endocrinology. 2013 Apr. 10, v. 368, no. 1-2

2013

Abstract	Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism.
Keywords	bile ; chenodeoxycholic acid ; cholesterol ; cholic acid ; deoxycholic acid ; enzymes ; gene expression ; glucose ; homeostasis ; lithocholic acid ; liver ; metabolites ; pharmacokinetics ; receptors ; signal transduction ; small intestine ; tissues ; transcription factors ; transporters ; vitamin D
Language	English
Dates of publication	2013-0410
Size	p. 17-29.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2012.05.004
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR.

Ay, Ümran / Leníček, Martin / Haider, Raphael S / Classen, Arno / van Eijk, Hans / Koelfat, Kiran V K / van der Kroft, Gregory / Neumann, Ulf P / Hoffmann, Carsten / Bolm, Carsten / Olde Damink, Steven W M / Schaap, Frank G

Hepatology communications

2024 Volume 8, Issue 4

Abstract: ... farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation.: Methods: N ... on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined. ... of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were ...

Abstract	Background: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. Methods: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. Results: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. Conclusions: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.
MeSH term(s)	Humans ; Bile/chemistry ; Bile Acids and Salts/pharmacology ; Bile Acids and Salts/metabolism ; Liver/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Transcription Factors ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Bile Acids and Salts ; Receptors, Cytoplasmic and Nuclear ; Transcription Factors ; GPBAR1 protein, human ; Receptors, G-Protein-Coupled ; farnesoid X-activated receptor (0C5V0MRU6P)
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article
ISSN	2471-254X
ISSN (online)	2471-254X
DOI	10.1097/HC9.0000000000000383
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Update on FXR Biology

Chang Yeob Han

International Journal of Molecular Sciences, Vol 19, Iss 7, p

Promising Therapeutic Target?

2018 Volume 2069

Abstract: ... of systemic FXR biology in various organs and the gut–liver axis, particularly regarding the recent ... the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19 ... Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance ...

Abstract	Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut–liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development.
Keywords	nuclear receptor ; FXR (farnesoid X receptor) ; liver diseases ; metabolic disorders ; pharmacological application ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Update on FXR Biology: Promising Therapeutic Target?

Han, Chang Yeob

International journal of molecular sciences

2018 Volume 19, Issue 7

Abstract: ... of systemic FXR biology in various organs and the gut⁻liver axis, particularly regarding the recent ... the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19 ... Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance ...

Abstract	Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut⁻liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Cardiovascular System/metabolism ; Cell Transformation, Neoplastic/metabolism ; Energy Metabolism ; Homeostasis ; Humans ; Kidney/metabolism ; Pancreas/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism
Chemical Substances	Receptors, Cytoplasmic and Nuclear ; farnesoid X-activated receptor
Language	English
Publishing date	2018-07-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19072069
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Article ; Online: FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway.

Jung, Dongju / York, J Philippe / Wang, Li / Yang, Chaofeng / Zhang, Aijun / Francis, Heather L / Webb, Paul / McKeehan, Wallace L / Alpini, Gianfranco / Lesage, Gene D / Moore, David D / Xia, Xuefeng

Pflugers Archiv : European journal of physiology

2013 Volume 466, Issue 5, Page(s) 1011–1019

Abstract: ... The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR ... a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing ... The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using ...

Abstract	Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver.
MeSH term(s)	Animals ; Bile Acids and Salts/metabolism ; Bile Ducts/cytology ; Bile Ducts/metabolism ; Cells, Cultured ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Epithelial Cells/metabolism ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism ; Hep G2 Cells ; Humans ; Mice ; Rats ; Receptor, Fibroblast Growth Factor, Type 4/genetics ; Receptor, Fibroblast Growth Factor, Type 4/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	Bile Acids and Salts ; Receptors, Cytoplasmic and Nuclear ; fibroblast growth factor 15, mouse ; farnesoid X-activated receptor (0C5V0MRU6P) ; Fibroblast Growth Factors (62031-54-3) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Fgfr4 protein, mouse (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 4 (EC 2.7.10.1) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2013-09-26
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-013-1364-3
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Article: FXR signaling in the enterohepatic system

Matsubara, Tsutomu / Li, Fei / Gonzalez, Frank J.

Molecular and cellular endocrinology

Volume v. 368,, Issue no. 1

Abstract	Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism.
Keywords	metabolites ; small intestine ; bile ; homeostasis ; cholic acid ; transcription factors ; receptors ; chenodeoxycholic acid ; signal transduction ; cholesterol ; enzymes ; transporters ; glucose ; liver ; gene expression ; lithocholic acid ; vitamin D ; pharmacokinetics ; deoxycholic acid ; tissues
Language	English
Document type	Article
ISSN	0303-7207
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article ; Online: FXR signaling in the enterohepatic system.

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Article: FXR signaling in the enterohepatic system

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Article ; Online: Microbially conjugated bile salts found in human bile activate the bile salt receptors TGR5 and FXR.

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Article ; Online: Update on FXR Biology

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Article ; Online: Update on FXR Biology: Promising Therapeutic Target?

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Article ; Online: FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway.

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Article: FXR signaling in the enterohepatic system

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