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SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway

Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in met...

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Autores principales: Leal, Helena, Cardoso, João, Valério, Patrícia, Quatorze, Marta, Carmona, Vítor, Cunha-Santos, Janete, Pereira de Almeida, Luís, Pereira, Cláudia, Cavadas, Cláudia, Gomes, Pedro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223775/
https://www.ncbi.nlm.nih.gov/pubmed/35743232
http://dx.doi.org/10.3390/ijms23126790
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author Leal, Helena
Cardoso, João
Valério, Patrícia
Quatorze, Marta
Carmona, Vítor
Cunha-Santos, Janete
Pereira de Almeida, Luís
Pereira, Cláudia
Cavadas, Cláudia
Gomes, Pedro
author_facet Leal, Helena
Cardoso, João
Valério, Patrícia
Quatorze, Marta
Carmona, Vítor
Cunha-Santos, Janete
Pereira de Almeida, Luís
Pereira, Cláudia
Cavadas, Cláudia
Gomes, Pedro
author_sort Leal, Helena
collection PubMed
description Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in metabolic homeostasis, but its role in the development of hepatic steatosis and its link with ER stress activation remains unknown. SIRT2-knockout (SIRT2-KO) and wild-type mice were fed either a control or a high-fat diet (HFD) for 4 weeks. Genetic manipulation of SIRT2 levels was performed in human hepatic cells. Although apparently normal under a control diet, SIRT2-KO mice showed accelerated body weight gain and adiposity on a HFD, accompanied by severe insulin resistance. Importantly, SIRT2-KO mice exhibited worsened hepatic steatosis independently from diet, consistent with upregulated gene expression of lipogenic enzymes and increased expression of ER stress markers. Exposure of hepatic cells to palmitate induced lipid accumulation, increased ER stress, and decreased SIRT2 expression. Moreover, SIRT2-silenced cells showed enhanced lipid accumulation and ER stress activation under basal conditions, whereas SIRT2 overexpression abrogated palmitate-induced lipid deposition and ER stress activation. Our findings reveal a role for SIRT2 in the regulation of hepatic lipid homeostasis, potentially through the ER stress response, suggesting that SIRT2 activation might constitute a therapeutic strategy against obesity and its metabolic complications.
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spelling pubmed-92237752022-06-24 SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway Leal, Helena Cardoso, João Valério, Patrícia Quatorze, Marta Carmona, Vítor Cunha-Santos, Janete Pereira de Almeida, Luís Pereira, Cláudia Cavadas, Cláudia Gomes, Pedro Int J Mol Sci Article Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in metabolic homeostasis, but its role in the development of hepatic steatosis and its link with ER stress activation remains unknown. SIRT2-knockout (SIRT2-KO) and wild-type mice were fed either a control or a high-fat diet (HFD) for 4 weeks. Genetic manipulation of SIRT2 levels was performed in human hepatic cells. Although apparently normal under a control diet, SIRT2-KO mice showed accelerated body weight gain and adiposity on a HFD, accompanied by severe insulin resistance. Importantly, SIRT2-KO mice exhibited worsened hepatic steatosis independently from diet, consistent with upregulated gene expression of lipogenic enzymes and increased expression of ER stress markers. Exposure of hepatic cells to palmitate induced lipid accumulation, increased ER stress, and decreased SIRT2 expression. Moreover, SIRT2-silenced cells showed enhanced lipid accumulation and ER stress activation under basal conditions, whereas SIRT2 overexpression abrogated palmitate-induced lipid deposition and ER stress activation. Our findings reveal a role for SIRT2 in the regulation of hepatic lipid homeostasis, potentially through the ER stress response, suggesting that SIRT2 activation might constitute a therapeutic strategy against obesity and its metabolic complications. MDPI 2022-06-17 /pmc/articles/PMC9223775/ /pubmed/35743232 http://dx.doi.org/10.3390/ijms23126790 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Leal, Helena
Cardoso, João
Valério, Patrícia
Quatorze, Marta
Carmona, Vítor
Cunha-Santos, Janete
Pereira de Almeida, Luís
Pereira, Cláudia
Cavadas, Cláudia
Gomes, Pedro
SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway
title SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway
title_full SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway
title_fullStr SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway
title_full_unstemmed SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway
title_short SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway
title_sort sirt2 deficiency exacerbates hepatic steatosis via a putative role of the er stress pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223775/
https://www.ncbi.nlm.nih.gov/pubmed/35743232
http://dx.doi.org/10.3390/ijms23126790
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