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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
Authors: 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.
Issue Date: 16-Jul-2022
Publisher: Elsevier
Project: info:eu-repo/grantAgreement/FCT/3599-PPCDT/EXPL/BIA-BQM/1361/2021 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04539/2020/PT 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP/04539/2020/PT 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/00081/2020/PT/Chemistry Research Unit of University of Porto 
info:eu-repo/grantAgreement/FCT/FARH/SFRH/BD/131070/2017/PT/MitoBULLET: Antioxidant Targeting of Mitochondria to Prevent Non-Alcoholic Fatty Liver Disease-induced Oxidative Stress and Inflammation 
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/BD/140817/2018/PT/mitoBone: Mitochondrial performance on osteoclast differentiation and biology during E2 deprivation – Innovative targets for osteoporosis treatment 
info:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH/BPD/116061/2016/PT/Exercising the Future: Voluntary Exercise During Gestational Diabetes to Improve Cardiac Function and Mitochondrial Function in the Offspring 
info:eu-repo/grantAgreement/FCT/POR_CENTRO/PD/BD/128254/2016/PT/mito Path: classifying mitoehondial traffiching pe hans in neurous by predictive phenot, pical analyis 
info:eu-repo/grantAgreement/EC/H2020/722619/EU/Bioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease 
info:eu-repo/grantAgreement/EC/H2020/734719/EU/mitoFOIE GRAS: Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease 
Serial title, monograph or event: Redox Biology
Volume: 55
Abstract: 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.
ISSN: 22132317
DOI: 10.1016/j.redox.2022.102400
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
IIIUC - Artigos em Revistas Internacionais
I&D CFE - Artigos em Revistas Internacionais
I&D MIA PORTUGAL - Artigos em Revistas Internacionais

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