Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology

Autores
Sookoian, Silvia Cristina; Pirola, Carlos José; Valenti, Luca; Davidson, Nicholas O.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This new prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as a NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de-novo lipogenesis; mitochondrial energy utilization; lipid droplet assembly, lipolytic catabolism and fatty acid compartmentalization; and VLDL assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and which influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Valenti, Luca. Università degli Studi di Milano; Italia
Fil: Davidson, Nicholas O.. University of Washington. School of Medicine; Estados Unidos
Materia
NAFLD
GENETICS
SYSTEMS BIOLOGY
REACTOME
Nivel de accesibilidad
acceso embargado
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/105167
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biologySookoian, Silvia CristinaPirola, Carlos JoséValenti, LucaDavidson, Nicholas O.NAFLDGENETICSSYSTEMS BIOLOGYREACTOMEhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This new prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as a NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de-novo lipogenesis; mitochondrial energy utilization; lipid droplet assembly, lipolytic catabolism and fatty acid compartmentalization; and VLDL assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and which influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Valenti, Luca. Università degli Studi di Milano; ItaliaFil: Davidson, Nicholas O.. University of Washington. School of Medicine; Estados UnidosJohn Wiley & Sons Inc2020-03-14info:eu-repo/date/embargoEnd/2020-09-15info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/105167Sookoian, Silvia Cristina; Pirola, Carlos José; Valenti, Luca; Davidson, Nicholas O.; Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology; John Wiley & Sons Inc; Hepatology (Baltimore, Md.); 14-3-2020; 1-380270-9139CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31229info:eu-repo/semantics/altIdentifier/doi/10.1002/hep.31229info:eu-repo/semantics/embargoedAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:26:11Zoai:ri.conicet.gov.ar:11336/105167instacron: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:34982025-10-15 14:26:12.237CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
title Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
spellingShingle Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
Sookoian, Silvia Cristina
NAFLD
GENETICS
SYSTEMS BIOLOGY
REACTOME
title_short Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
title_full Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
title_fullStr Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
title_full_unstemmed Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
title_sort Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology
dc.creator.none.fl_str_mv Sookoian, Silvia Cristina
Pirola, Carlos José
Valenti, Luca
Davidson, Nicholas O.
author Sookoian, Silvia Cristina
author_facet Sookoian, Silvia Cristina
Pirola, Carlos José
Valenti, Luca
Davidson, Nicholas O.
author_role author
author2 Pirola, Carlos José
Valenti, Luca
Davidson, Nicholas O.
author2_role author
author
author
dc.subject.none.fl_str_mv NAFLD
GENETICS
SYSTEMS BIOLOGY
REACTOME
topic NAFLD
GENETICS
SYSTEMS BIOLOGY
REACTOME
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This new prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as a NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de-novo lipogenesis; mitochondrial energy utilization; lipid droplet assembly, lipolytic catabolism and fatty acid compartmentalization; and VLDL assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and which influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Valenti, Luca. Università degli Studi di Milano; Italia
Fil: Davidson, Nicholas O.. University of Washington. School of Medicine; Estados Unidos
description Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This new prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as a NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de-novo lipogenesis; mitochondrial energy utilization; lipid droplet assembly, lipolytic catabolism and fatty acid compartmentalization; and VLDL assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and which influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
publishDate 2020
dc.date.none.fl_str_mv 2020-03-14
info:eu-repo/date/embargoEnd/2020-09-15
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/11336/105167
Sookoian, Silvia Cristina; Pirola, Carlos José; Valenti, Luca; Davidson, Nicholas O.; Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology; John Wiley & Sons Inc; Hepatology (Baltimore, Md.); 14-3-2020; 1-38
0270-9139
CONICET Digital
CONICET
url http://hdl.handle.net/11336/105167
identifier_str_mv Sookoian, Silvia Cristina; Pirola, Carlos José; Valenti, Luca; Davidson, Nicholas O.; Genetic pathways in nonalcoholic fatty liver disease: Insights from systems biology; John Wiley & Sons Inc; Hepatology (Baltimore, Md.); 14-3-2020; 1-38
0270-9139
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://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31229
info:eu-repo/semantics/altIdentifier/doi/10.1002/hep.31229
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv embargoedAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons Inc
publisher.none.fl_str_mv John Wiley & Sons Inc
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 12.891075

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