Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes

<i>Background and Objectives</i>: Osteoarthritis (OA) is one of the most common and highly prevalent types of arthritis, also considered a multiphenotypic disease with a strong metabolic component. Ageing is the primary risk factor for OA, while the age-related decline in autophagic acti...

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Autores principales:	Aliki-Alexandra Papageorgiou, Andreas Goutas, Varvara Trachana, Aspasia Tsezou
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	osteoarthritis sirtuin 1 lipid metabolism autophagy Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/3ebbeebd79c0461e9a3c5b130a68f66a
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spelling	oai:doaj.org-article:3ebbeebd79c0461e9a3c5b130a68f66a2021-11-25T18:18:33ZDual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes10.3390/medicina571112031648-91441010-660Xhttps://doaj.org/article/3ebbeebd79c0461e9a3c5b130a68f66a2021-11-01T00:00:00Zhttps://www.mdpi.com/1648-9144/57/11/1203https://doaj.org/toc/1010-660Xhttps://doaj.org/toc/1648-9144<i>Background and Objectives</i>: Osteoarthritis (OA) is one of the most common and highly prevalent types of arthritis, also considered a multiphenotypic disease with a strong metabolic component. Ageing is the primary risk factor for OA, while the age-related decline in autophagic activity affects cell function and chondrocyte homeostasis. The aim of this study was to investigate the role of sirtuin 1 (SIRT1) in autophagy dysregulation and lipid metabolism in human OA chondrocytes. <i>Materials and Methods</i>: OA chondrocytes were treated with Resveratrol, Hydroxycloroquine (HCQ) or 3-Methyladenine (3-MA) and HCQ or 3-MA followed by siRNA against SIRT1 (siSIRT1). Then, SIRT1, AcNF-κBp65, LOX-1 and autophagy-related proteins ATG5, ATG13, PI3K class III, Beclin-1, LC3 and ULK protein levels were evaluated using Western blot. Normal articular chondrocytes were treated under serum starvation and/or siSIRT1, and the protein expression levels of the above autophagy-related proteins were evaluated. The staining patterns of LC3/p62 and LOX-1 were analyzed microscopically by immunofluorescence. SIRT1/LC3 complex formation was analyzed by immunoprecipitation. <i>Results</i>: SIRT1 and LOX-1 protein expression were negatively correlated in OA chondrocytes. SIRT1 regulated LOX-1 expression via NF-κΒ deacetylation, while treatment with Resveratrol enhanced SIRT1 enzymatic activity, resulting in LOX-1 downregulation and autophagy induction. In OA chondrocytes, SIRT1 was recognized as an autophagy substrate, formed a complex with LC3 and was consequently subjected to cytoplasmic autophagosome-lysosome degradation. Moreover, siSIRT1-treated normal chondrocytes showed decreased autophagic activity, while double-treated (siSIRT1 and serum starvation) cells showed no induction of autophagy. <i>Conclusions</i>: Our results suggest that SIRT1 regulates lipid homeostasis through LOX-1 expression regulation. Additionally, we indicate that the necessity of SIRT1 for autophagy induction in normal chondrocytes, together with its selective autophagic degradation in OA chondrocytes, could contribute to autophagy dysregulation in OA. We, therefore, suggest a novel regulatory scheme that functionally connects lipid metabolism and autophagy in late-stage OA.Aliki-Alexandra PapageorgiouAndreas GoutasVarvara TrachanaAspasia TsezouMDPI AGarticleosteoarthritissirtuin 1lipid metabolismautophagyMedicine (General)R5-920ENMedicina, Vol 57, Iss 1203, p 1203 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	osteoarthritis sirtuin 1 lipid metabolism autophagy Medicine (General) R5-920
spellingShingle	osteoarthritis sirtuin 1 lipid metabolism autophagy Medicine (General) R5-920 Aliki-Alexandra Papageorgiou Andreas Goutas Varvara Trachana Aspasia Tsezou Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes
description	<i>Background and Objectives</i>: Osteoarthritis (OA) is one of the most common and highly prevalent types of arthritis, also considered a multiphenotypic disease with a strong metabolic component. Ageing is the primary risk factor for OA, while the age-related decline in autophagic activity affects cell function and chondrocyte homeostasis. The aim of this study was to investigate the role of sirtuin 1 (SIRT1) in autophagy dysregulation and lipid metabolism in human OA chondrocytes. <i>Materials and Methods</i>: OA chondrocytes were treated with Resveratrol, Hydroxycloroquine (HCQ) or 3-Methyladenine (3-MA) and HCQ or 3-MA followed by siRNA against SIRT1 (siSIRT1). Then, SIRT1, AcNF-κBp65, LOX-1 and autophagy-related proteins ATG5, ATG13, PI3K class III, Beclin-1, LC3 and ULK protein levels were evaluated using Western blot. Normal articular chondrocytes were treated under serum starvation and/or siSIRT1, and the protein expression levels of the above autophagy-related proteins were evaluated. The staining patterns of LC3/p62 and LOX-1 were analyzed microscopically by immunofluorescence. SIRT1/LC3 complex formation was analyzed by immunoprecipitation. <i>Results</i>: SIRT1 and LOX-1 protein expression were negatively correlated in OA chondrocytes. SIRT1 regulated LOX-1 expression via NF-κΒ deacetylation, while treatment with Resveratrol enhanced SIRT1 enzymatic activity, resulting in LOX-1 downregulation and autophagy induction. In OA chondrocytes, SIRT1 was recognized as an autophagy substrate, formed a complex with LC3 and was consequently subjected to cytoplasmic autophagosome-lysosome degradation. Moreover, siSIRT1-treated normal chondrocytes showed decreased autophagic activity, while double-treated (siSIRT1 and serum starvation) cells showed no induction of autophagy. <i>Conclusions</i>: Our results suggest that SIRT1 regulates lipid homeostasis through LOX-1 expression regulation. Additionally, we indicate that the necessity of SIRT1 for autophagy induction in normal chondrocytes, together with its selective autophagic degradation in OA chondrocytes, could contribute to autophagy dysregulation in OA. We, therefore, suggest a novel regulatory scheme that functionally connects lipid metabolism and autophagy in late-stage OA.
format	article
author	Aliki-Alexandra Papageorgiou Andreas Goutas Varvara Trachana Aspasia Tsezou
author_facet	Aliki-Alexandra Papageorgiou Andreas Goutas Varvara Trachana Aspasia Tsezou
author_sort	Aliki-Alexandra Papageorgiou
title	Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes
title_short	Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes
title_full	Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes
title_fullStr	Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes
title_full_unstemmed	Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes
title_sort	dual role of sirt1 in autophagy and lipid metabolism regulation in osteoarthritic chondrocytes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3ebbeebd79c0461e9a3c5b130a68f66a
work_keys_str_mv	AT alikialexandrapapageorgiou dualroleofsirt1inautophagyandlipidmetabolismregulationinosteoarthriticchondrocytes AT andreasgoutas dualroleofsirt1inautophagyandlipidmetabolismregulationinosteoarthriticchondrocytes AT varvaratrachana dualroleofsirt1inautophagyandlipidmetabolismregulationinosteoarthriticchondrocytes AT aspasiatsezou dualroleofsirt1inautophagyandlipidmetabolismregulationinosteoarthriticchondrocytes
_version_	1718411314243567616

Dual Role of SIRT1 in Autophagy and Lipid Metabolism Regulation in Osteoarthritic Chondrocytes

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