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Cited by 48Liver Disease Diagnosis and TreatmentMitochondrial Function and PathologyDrug-Induced Hepatotoxicity and Protection

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

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Amorim, Ricardo, Simões, Inês C.M., Teixeira, José, Cagide, Fernando, Potes, Yaiza, Soares, Pedro, Carvalho, Adriana, Tavares, Ludgero C. +14 more·2022·Redox Biology
DOI 10.1016/j.redox.2022.102400PMC PMC9304680
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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 (AntiOxCIN 4 ) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN 4 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, AntiOxCIN 4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN 4 (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 AntiOxCIN 4 (100 μM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 μM, 24 h) were used for complementary studies. AntiOxCIN 4 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 AntiOxCIN 4 -induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN 4 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. AntiOxCIN 4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN 4 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 AntiOxCIN 4 in the prevention/treatment of NAFLD. • Mitochondriotropic anti-oxidant AntiOxCIN 4 ameliorate NAFLD phenotype of WD-fed mice. • AntiOxCIN 4 decreases lipid accumulation upregulating mitochondrial fatty acid oxidation. • AntiOxCIN 4 improves mitochondrial function by remodeling SIRT3-mediated metabolism. • AntiOxCIN 4 upregulated anti-oxidant defense system to counteract oxidative stress. • AntiOxCIN 4 prevented lipid accumulation-driven autophagic flux impairment.

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  • To induce steatosis in HepG2, supraphysiological concentrations of FFAs (0.5-2.0 mM) are often used.

    “Second, to induce steatosis, supraphysiological concentrations of FFAs (concentrations of 0.5–2.0 mM) are often used in HepG2 experiments [28,91,125,126,127,128,129,130].”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [130]

    The Results (page unavailable) describe supraphysiological FFA exposure in HepG2 cells and report increased neutral lipid content. However, the Materials and methods (page unavailable) specify 250 μM (0.25 mM), not 0.5–2.0 mM, and the paper does not establish that the claimed range is often used. (LLM, conf=0.86)

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Authors
Amorim, R., Simões, I. C. M., Teixeira, J., Cagide, F., Potes, Y., Soares, P., Carvalho, A., Tavares, L. C., Benfeito, S., Pereira, S. P., Simões, R. F., Karkucinska-Wieckowska, A., Viegas, I., Szymanska, S., Dąbrowski, M., Janikiewicz, J., Cunha-Oliveira, T., Dobrzyń, A., Jones, J. G., Borges, F., Wieckowski, M. R., & Oliveira, P. J.
Affiliations
  • Universidade do Porto (PT)
  • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
  • Centro de Inovação em Biomedicina e Biotecnologia (PT)
  • Centro de Neurociências e Biologia Celular (PT)
  • Escola Universitária Vasco da Gama (PT)
Corresponding author
Borges, Fernanda
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2022-09
Volume
55
Pages
102400
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2022.102400
PMC
PMC9304680
OpenAlex
W4285678449
Cited by
48
References
51
Citations by year
2026: 13 · 2025: 12 · 2024: 14 · 2023: 9
FWCI
6.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Estudo Geral (Universidad de Coimbra) (submittedVersion, cc-by-nc-nd)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
Funders
  • European Regional Development Fund
  • Programa Operacional Temático Factores de Competitividade
  • H2020 Marie Skłodowska-Curie Actions
  • National Science Centre Poland (UMO-2018/29/B/NZ1/00589, UMO-2020/36/T/NZ1/00004)
  • European Commission Marie Sklodowska-Curie Actions (722619, 734719)
  • Sociedade Portuguesa de Pediatria (2020.01560)
  • Fundação para a Ciência e a Tecnologia (POCI-01-0145-FEDER-028607, PTDC/BIA-MOL/28607/2017, UIDP/04539/2020, POCI-01-0145-FEDER-029297, SFRH/BD/131070/2017, PD/BD/128254/2016, SFRH/BD/140817/2018, SFRH/BPD/116061/2016, DL57/2016/CP1448/CT0016)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
mitochondria-targeted antioxidants, non-alcoholic fatty liver disease, hepatic steatosis, fatty acid oxidation, mitochondrial oxidative phosphorylation, Nrf2/Keap1 pathway, mitophagy, autophagy, lipid accumulation, fatty acyl chain composition, mitochondrial dysfunction, oxidative stress, Western diet, HepG2 cells

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