Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with con...

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Autores: Prieur, Xavier, Lesnik, Philipp, Moreau, Martine, Rodríguez Rubio, Joan Carles, Doucet, Chantal, Chapman, M. John, Huby, Thierry
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2009
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/104862
Acesso em linha:https://hdl.handle.net/2445/104862
Access Level:acceso abierto
Palavra-chave:Expressió gènica
Triglicèrids
Apoproteïnes
Gene expression
Triglycerides
Apolipoproteins
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spelling Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in micePrieur, XavierLesnik, PhilippMoreau, MartineRodríguez Rubio, Joan CarlesDoucet, ChantalChapman, M. JohnHuby, ThierryExpressió gènicaTriglicèridsApoproteïnesGene expressionTriglyceridesApolipoproteinsMice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.Elsevier B.V.2009info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/104862Articles publicats en revistes (Bioquímica i Fisiologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1016/j.bbalip.2009.03.015Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2009, vol. 1791, num. 8, p. 764-771https://doi.org/10.1016/j.bbalip.2009.03.015(c) Elsevier B.V., 2009info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1048622026-05-27T06:46:51Z
dc.title.none.fl_str_mv Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
title Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
spellingShingle Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
Prieur, Xavier
Expressió gènica
Triglicèrids
Apoproteïnes
Gene expression
Triglycerides
Apolipoproteins
title_short Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
title_full Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
title_fullStr Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
title_full_unstemmed Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
title_sort Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
dc.creator.none.fl_str_mv Prieur, Xavier
Lesnik, Philipp
Moreau, Martine
Rodríguez Rubio, Joan Carles
Doucet, Chantal
Chapman, M. John
Huby, Thierry
author Prieur, Xavier
author_facet Prieur, Xavier
Lesnik, Philipp
Moreau, Martine
Rodríguez Rubio, Joan Carles
Doucet, Chantal
Chapman, M. John
Huby, Thierry
author_role author
author2 Lesnik, Philipp
Moreau, Martine
Rodríguez Rubio, Joan Carles
Doucet, Chantal
Chapman, M. John
Huby, Thierry
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Expressió gènica
Triglicèrids
Apoproteïnes
Gene expression
Triglycerides
Apolipoproteins
topic Expressió gènica
Triglicèrids
Apoproteïnes
Gene expression
Triglycerides
Apolipoproteins
description Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.
publishDate 2009
dc.date.none.fl_str_mv 2009
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/104862
url https://hdl.handle.net/2445/104862
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.bbalip.2009.03.015
Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2009, vol. 1791, num. 8, p. 764-771
https://doi.org/10.1016/j.bbalip.2009.03.015
dc.rights.none.fl_str_mv (c) Elsevier B.V., 2009
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Elsevier B.V., 2009
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Fisiologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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