Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/100998 https://doi.org/10.1016/j.redox.2022.102400 |
Resumo: | Non-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP+), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN4) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN4 (100 μM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 μM, 24 h) were used for complementary studies. AntiOxCIN4 decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN4-induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN4 also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1α-SIRT3 axis. AntiOxCIN4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN4 improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN4 in the prevention/treatment of NAFLD. |
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Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systemsNon-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP+), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN4) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN4 (100 μM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 μM, 24 h) were used for complementary studies. AntiOxCIN4 decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN4-induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN4 also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1α-SIRT3 axis. AntiOxCIN4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN4 improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN4 in the prevention/treatment of NAFLD.This work was funded by FEDER funds through the Operational Programme Competitiveness Factors (COMPETE) and the Foundation for Science and Technology (FCT): EXPL/BIA-BQM/1361/2021, PTDC/BIA-MOL/28607/2017, POCI-01-0145-FEDER-028607, PTDC/BTM-SAL/29297/2017, POCI-01-0145-FEDER-029297, UIDB/04539/2020, UIDP/04539/2020 and UIDP/QUI/00081/2020). Support for RA (SFRH/BD/131070/2017), AC (SFRH/BD/140817/2018), RFS (SFRH/BPD/116061/2016) and SPP (PD/BD/128254/2016) was provided by FCT, POPH and QREN. JT (2020.01560.CEECIND) and TCO (DL57/2016/CP1448/CT0016) acknowledges FCT, I.P. for the research contracts. MRW was supported by the National Science Centre, Poland (grant UMO-2018/29/B/NZ1/00589). ICMS was supported by the National Science Centre (grant UMO-2020/36/T/NZ1/00004). Additionally, I.C.M.S., J.G.J, M.R.W. and P.J.O. gratefully acknowledge the financial support for this research from the FOIE GRAS and mtFOIE GRAS projects. These projects received funding from the European Union's Horizon 2020 Research and Innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 722619 (FOIE GRAS) and Grant Agreement No. 734719 (mtFOIE GRAS). We also acknowledge the DMPK team led by Professor Kevin Read from the Wellcome Centre for Anti-Infectives Research (WCAIR) at the School of Life Sciences of the University of Dundee for performing the studies of AntiOxCin4 stability in water. Fig. 7 was drawn with BioRender software.Elsevier2022-07-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/100998http://hdl.handle.net/10316/100998https://doi.org/10.1016/j.redox.2022.102400eng22132317Amorim, RicardoSimões, Inês C. M.Teixeira, JoséCagide, FernandoPotes, YaizaSoares, PedroCarvalho, AdrianaTavares, Ludgero C.Benfeito, SofiaPereira, Susana P.Simões, Rui F.Karkucinska-Wieckowska, AgnieszkaViegas, IvanSzymanska, SylwiaDąbrowski, MichałJanikiewicz, JustynaCunha-Oliveira, TeresaDobrzyń, AgnieszkaJones, John GriffithBorges, FernandaWieckowski, Mariusz R.Oliveira, Paulo J.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-02-16T09:08:21Zoai:estudogeral.uc.pt:10316/100998Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:18:15.810161Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
title |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
spellingShingle |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems Amorim, Ricardo |
title_short |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
title_full |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
title_fullStr |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
title_full_unstemmed |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
title_sort |
Mitochondria-targeted anti-oxidant AntiOxCIN4 improved liver steatosis in Western diet-fed mice by preventing lipid accumulation due to upregulation of fatty acid oxidation, quality control mechanism and antioxidant defense systems |
author |
Amorim, Ricardo |
author_facet |
Amorim, Ricardo Simões, Inês C. M. Teixeira, José Cagide, Fernando Potes, Yaiza Soares, Pedro Carvalho, Adriana Tavares, Ludgero C. Benfeito, Sofia Pereira, Susana P. Simões, Rui F. Karkucinska-Wieckowska, Agnieszka Viegas, Ivan Szymanska, Sylwia Dąbrowski, Michał Janikiewicz, Justyna Cunha-Oliveira, Teresa Dobrzyń, Agnieszka Jones, John Griffith Borges, Fernanda Wieckowski, Mariusz R. Oliveira, Paulo J. |
author_role |
author |
author2 |
Simões, Inês C. M. Teixeira, José Cagide, Fernando Potes, Yaiza Soares, Pedro Carvalho, Adriana Tavares, Ludgero C. Benfeito, Sofia Pereira, Susana P. Simões, Rui F. Karkucinska-Wieckowska, Agnieszka Viegas, Ivan Szymanska, Sylwia Dąbrowski, Michał Janikiewicz, Justyna Cunha-Oliveira, Teresa Dobrzyń, Agnieszka Jones, John Griffith Borges, Fernanda Wieckowski, Mariusz R. Oliveira, Paulo J. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Amorim, Ricardo Simões, Inês C. M. Teixeira, José Cagide, Fernando Potes, Yaiza Soares, Pedro Carvalho, Adriana Tavares, Ludgero C. Benfeito, Sofia Pereira, Susana P. Simões, Rui F. Karkucinska-Wieckowska, Agnieszka Viegas, Ivan Szymanska, Sylwia Dąbrowski, Michał Janikiewicz, Justyna Cunha-Oliveira, Teresa Dobrzyń, Agnieszka Jones, John Griffith Borges, Fernanda Wieckowski, Mariusz R. Oliveira, Paulo J. |
description |
Non-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP+), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN4) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN4 (100 μM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 μM, 24 h) were used for complementary studies. AntiOxCIN4 decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN4-induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN4 also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1α-SIRT3 axis. AntiOxCIN4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN4 improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN4 in the prevention/treatment of NAFLD. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-07-16 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/100998 http://hdl.handle.net/10316/100998 https://doi.org/10.1016/j.redox.2022.102400 |
url |
http://hdl.handle.net/10316/100998 https://doi.org/10.1016/j.redox.2022.102400 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
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22132317 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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