• Je něco špatně v tomto záznamu ?

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

J. Skoda, K. Dohnalova, K. Chalupsky, A. Stahl, M. Templin, J. Maixnerova, S. Micuda, L. Grøntved, A. Braeuning, P. Pavek

. 2022 ; 197 (-) : 114905. [pub] 20211228

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22010818

The constitutive androstane receptor (CAR) controls xenobiotic clearance, regulates liver glucose, lipid metabolism, and energy homeostasis. These functions have been mainly discovered using the prototypical mouse-specific CAR ligand TCPOBOP in wild-type or CAR null mice. However, TCPOBOP is reported to result in some off-target metabolic effects in CAR null mice. In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyses in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the model, human CAR retains its constitutive activity in metabolism regulation; however, it is not activated by TCPOBOB. Notably, we observed that TCPOBOP affected lipid homeostasis by elevating serum and liver triglyceride levels and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and decrease of its metabolites in humanized CAR mice. RNA-seq analysis has shown divergent gene expression levels in wild-type and humanized CAR mice. Gene expression regulation in humanized mice is mainly involved in lipid metabolic processes and in the PPAR, leptin, thyroid, and circadian clock pathways. In contrast, CAR activation by TCPOBOP in wild-type mice reduced liver and plasma triglyceride levels and induced a typical transcriptomic proliferative response in the liver. In summary, we identified TCPOBOP as a disruptor of lipid metabolism in humanized CAR mice. The divergent effects of TCPOBOP in humanized mice in comparison with the prototypical CAR-mediated response in WT mice warrant the use of appropriate model ligands and humanized animal models during the testing of endocrine disruption and the characterization of adverse outcome pathways.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22010818
003      
CZ-PrNML
005      
20220506125811.0
007      
ta
008      
220425s2022 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.bcp.2021.114905 $2 doi
035    __
$a (PubMed)34971590
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Skoda, Josef $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
245    10
$a Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice / $c J. Skoda, K. Dohnalova, K. Chalupsky, A. Stahl, M. Templin, J. Maixnerova, S. Micuda, L. Grøntved, A. Braeuning, P. Pavek
520    9_
$a The constitutive androstane receptor (CAR) controls xenobiotic clearance, regulates liver glucose, lipid metabolism, and energy homeostasis. These functions have been mainly discovered using the prototypical mouse-specific CAR ligand TCPOBOP in wild-type or CAR null mice. However, TCPOBOP is reported to result in some off-target metabolic effects in CAR null mice. In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyses in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the model, human CAR retains its constitutive activity in metabolism regulation; however, it is not activated by TCPOBOB. Notably, we observed that TCPOBOP affected lipid homeostasis by elevating serum and liver triglyceride levels and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and decrease of its metabolites in humanized CAR mice. RNA-seq analysis has shown divergent gene expression levels in wild-type and humanized CAR mice. Gene expression regulation in humanized mice is mainly involved in lipid metabolic processes and in the PPAR, leptin, thyroid, and circadian clock pathways. In contrast, CAR activation by TCPOBOP in wild-type mice reduced liver and plasma triglyceride levels and induced a typical transcriptomic proliferative response in the liver. In summary, we identified TCPOBOP as a disruptor of lipid metabolism in humanized CAR mice. The divergent effects of TCPOBOP in humanized mice in comparison with the prototypical CAR-mediated response in WT mice warrant the use of appropriate model ligands and humanized animal models during the testing of endocrine disruption and the characterization of adverse outcome pathways.
650    _2
$a zvířata $7 D000818
650    _2
$a konstitutivní androstanový receptor $x agonisté $x metabolismus $7 D000090702
650    _2
$a lidé $7 D006801
650    _2
$a metabolismus lipidů $x účinky léků $x fyziologie $7 D050356
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a myši $7 D051379
650    _2
$a myši inbrední C57BL $7 D008810
650    _2
$a myši transgenní $7 D008822
650    _2
$a pyridiny $x aplikace a dávkování $7 D011725
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Dohnalova, Klara $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; First Faculty of Medicine, Charles University, Katerinska 32, 121 08 Prague, Czech Republic
700    1_
$a Chalupsky, Karel $u Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic
700    1_
$a Stahl, Aaron $u NMI - Natural and Medical Sciences Institute at the University of Tuebingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
700    1_
$a Templin, Markus $u NMI - Natural and Medical Sciences Institute at the University of Tuebingen, Markwiesenstr. 55, 72770 Reutlingen, Germany
700    1_
$a Maixnerova, Jana $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
700    1_
$a Micuda, Stanislav $u Department of Pharmacology, Medical Faculty in Hradec Kralove, Charles University, Simkova 870, 500 03 Hradec Kralove, Czech Republic
700    1_
$a Grøntved, Lars $u Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense M 5230, Denmark
700    1_
$a Braeuning, Albert $u Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin 10589, Germany
700    1_
$a Pavek, Petr $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Electronic address: petr.pavek@faf.cuni.cz
773    0_
$w MED00000704 $t Biochemical pharmacology $x 1873-2968 $g Roč. 197, č. - (2022), s. 114905
856    41
$u https://pubmed.ncbi.nlm.nih.gov/34971590 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220425 $b ABA008
991    __
$a 20220506125803 $b ABA008
999    __
$a ok $b bmc $g 1788777 $s 1162016
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2022 $b 197 $c - $d 114905 $e 20211228 $i 1873-2968 $m Biochemical pharmacology $n Biochem Pharmacol $x MED00000704
LZP    __
$a Pubmed-20220425
Zpět

Najít záznam

Citační ukazatele

Možnosti archivace