Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a

Autores
Brie, Belen; Sarmento Cabral, Andre; Pascual, Florencia Lilian; Cordoba Chacon, Jose; Kineman, Rhonda Denise; Becu, Damasia
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Growth hormone (GH) modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; thus, GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13, Asns, and Cyp7b1, and the female-predominant genes Hao2, Pgc1a, Hamp2, Cyp2a4, and Cyp2b9. We explored mRNA expression in 2 settings: (i) intact liver GH receptor (GHR) but altered GH and insulin-like growth factor 1 (IGF1) levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines); and (ii) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao, Cyp2a4, and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice) and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIGF1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn13, Asns, Cyp7b1, Hao2, Hamp2, Pgc1a, Cyp2a4, and Cyp2b9 in a sex- and gene-specific manner.
Fil: Brie, Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Sarmento Cabral, Andre. University of Illinois; Estados Unidos
Fil: Pascual, Florencia Lilian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Cordoba Chacon, Jose. University of Illinois; Estados Unidos
Fil: Kineman, Rhonda Denise. University of Illinois; Estados Unidos. Jesse Brown Veterans Affairs Medical Center; Estados Unidos
Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Materia
GROWTH HORMONE
LIVER
SEXUAL DIMORPHISM
STAT5b
STAT
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/243681
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/243681
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1aBrie, BelenSarmento Cabral, AndrePascual, Florencia LilianCordoba Chacon, JoseKineman, Rhonda DeniseBecu, DamasiaGROWTH HORMONELIVERSEXUAL DIMORPHISMSTAT5bSTAThttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Growth hormone (GH) modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; thus, GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13, Asns, and Cyp7b1, and the female-predominant genes Hao2, Pgc1a, Hamp2, Cyp2a4, and Cyp2b9. We explored mRNA expression in 2 settings: (i) intact liver GH receptor (GHR) but altered GH and insulin-like growth factor 1 (IGF1) levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines); and (ii) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao, Cyp2a4, and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice) and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIGF1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn13, Asns, Cyp7b1, Hao2, Hamp2, Pgc1a, Cyp2a4, and Cyp2b9 in a sex- and gene-specific manner.Fil: Brie, Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sarmento Cabral, Andre. University of Illinois; Estados UnidosFil: Pascual, Florencia Lilian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Cordoba Chacon, Jose. University of Illinois; Estados UnidosFil: Kineman, Rhonda Denise. University of Illinois; Estados Unidos. Jesse Brown Veterans Affairs Medical Center; Estados UnidosFil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaEndocrine Society2024-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/243681Brie, Belen; Sarmento Cabral, Andre; Pascual, Florencia Lilian; Cordoba Chacon, Jose; Kineman, Rhonda Denise; et al.; Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a; Endocrine Society; Journal of the Endocrine Society; 8; 3; 3-2024; 1-162472-1972CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jes/article/doi/10.1210/jendso/bvae015/7595706info:eu-repo/semantics/altIdentifier/doi/10.1210/jendso/bvae015info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:49:02Zoai:ri.conicet.gov.ar:11336/243681instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:49:03.02CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
title Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
spellingShingle Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
Brie, Belen
GROWTH HORMONE
LIVER
SEXUAL DIMORPHISM
STAT5b
STAT
title_short Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
title_full Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
title_fullStr Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
title_full_unstemmed Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
title_sort Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a
dc.creator.none.fl_str_mv Brie, Belen
Sarmento Cabral, Andre
Pascual, Florencia Lilian
Cordoba Chacon, Jose
Kineman, Rhonda Denise
Becu, Damasia
author Brie, Belen
author_facet Brie, Belen
Sarmento Cabral, Andre
Pascual, Florencia Lilian
Cordoba Chacon, Jose
Kineman, Rhonda Denise
Becu, Damasia
author_role author
author2 Sarmento Cabral, Andre
Pascual, Florencia Lilian
Cordoba Chacon, Jose
Kineman, Rhonda Denise
Becu, Damasia
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv GROWTH HORMONE
LIVER
SEXUAL DIMORPHISM
STAT5b
STAT
topic GROWTH HORMONE
LIVER
SEXUAL DIMORPHISM
STAT5b
STAT
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Growth hormone (GH) modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; thus, GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13, Asns, and Cyp7b1, and the female-predominant genes Hao2, Pgc1a, Hamp2, Cyp2a4, and Cyp2b9. We explored mRNA expression in 2 settings: (i) intact liver GH receptor (GHR) but altered GH and insulin-like growth factor 1 (IGF1) levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines); and (ii) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao, Cyp2a4, and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice) and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIGF1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn13, Asns, Cyp7b1, Hao2, Hamp2, Pgc1a, Cyp2a4, and Cyp2b9 in a sex- and gene-specific manner.
Fil: Brie, Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Sarmento Cabral, Andre. University of Illinois; Estados Unidos
Fil: Pascual, Florencia Lilian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Cordoba Chacon, Jose. University of Illinois; Estados Unidos
Fil: Kineman, Rhonda Denise. University of Illinois; Estados Unidos. Jesse Brown Veterans Affairs Medical Center; Estados Unidos
Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
description Growth hormone (GH) modifies liver gene transcription in a sexually dimorphic manner to meet liver metabolic demands related to sex; thus, GH dysregulation leads to sex-biased hepatic disease. We dissected the steps of the GH regulatory cascade modifying GH-dependent genes involved in metabolism, focusing on the male-predominant genes Lcn13, Asns, and Cyp7b1, and the female-predominant genes Hao2, Pgc1a, Hamp2, Cyp2a4, and Cyp2b9. We explored mRNA expression in 2 settings: (i) intact liver GH receptor (GHR) but altered GH and insulin-like growth factor 1 (IGF1) levels (NeuroDrd2KO, HiGH, aHepIGF1kd, and STAT5bCA mouse lines); and (ii) liver loss of GHR, with or without STAT5b reconstitution (aHepGHRkd, and aHepGHRkd + STAT5bCA). Lcn13 was downregulated in males in most models, while Asns and Cyp7b1 were decreased in males by low GH levels or action, or constant GH levels, but unexpectedly upregulated in both sexes by the loss of liver Igf1 or constitutive Stat5b expression. Hao, Cyp2a4, and Cyp2b9 were generally decreased in female mice with low GH levels or action (NeuroDrd2KO and/or aHepGHRkd mice) and increased in HiGH females, while in contrast, Pgc1a was increased in female NeuroDrd2KO but decreased in STAT5bCA and aHepIGF1kd females. Bioinformatic analysis of RNAseq from aHepGHRkd livers stressed the greater impact of GHR loss on wide gene expression in males and highlighted that GH modifies almost completely different gene signatures in each sex. Concordantly, we show that altering different steps of the GH cascade in the liver modified liver expression of Lcn13, Asns, Cyp7b1, Hao2, Hamp2, Pgc1a, Cyp2a4, and Cyp2b9 in a sex- and gene-specific manner.
publishDate 2024
dc.date.none.fl_str_mv 2024-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/243681
Brie, Belen; Sarmento Cabral, Andre; Pascual, Florencia Lilian; Cordoba Chacon, Jose; Kineman, Rhonda Denise; et al.; Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a; Endocrine Society; Journal of the Endocrine Society; 8; 3; 3-2024; 1-16
2472-1972
CONICET Digital
CONICET
url http://hdl.handle.net/11336/243681
identifier_str_mv Brie, Belen; Sarmento Cabral, Andre; Pascual, Florencia Lilian; Cordoba Chacon, Jose; Kineman, Rhonda Denise; et al.; Modifications of the GH Axis Reveal Unique Sexually Dimorphic Liver Signatures for Lcn13 , Asns , Hamp2 , Hao2 , and Pgc1a; Endocrine Society; Journal of the Endocrine Society; 8; 3; 3-2024; 1-16
2472-1972
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jes/article/doi/10.1210/jendso/bvae015/7595706
info:eu-repo/semantics/altIdentifier/doi/10.1210/jendso/bvae015
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Endocrine Society
publisher.none.fl_str_mv Endocrine Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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