(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease

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Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play significant roles in NAFLD pathogenesis. The unfolded protein response in mitochondria (UPRmt) is an adaptive mechanism that aims to restore mitochondrial protein homeostasis and mitigate cellular stress. This study aimed to investigate the effects of ( +)-Lipoic acid (ALA) on UPRmt, inflammation, and oxidative stress in an in vitro model of NAFLD using HepG2 cells treated with palmitic acid and oleic acid to induce steatosis.

Results

Treatment with palmitic and oleic acids increased UPRmt-related proteins HSP90 and HSP60 (heat shock protein), and decreased CLPP (caseinolytic protease P), indicating ER stress activation. ALA treatment at 1 μM and 5 μM restored UPRmt-related protein levels. PA:OA (palmitic acid:oleic acid)-induced ER stress markers IRE1α (Inositol requiring enzyme-1), CHOP (C/EBP Homologous Protein), BIP (Binding Immunoglobulin Protein), and BAX (Bcl-2-associated X protein) were significantly reduced by ALA treatment. ALA also enhanced ER-mediated protein glycosylation and reduced oxidative stress, as evidenced by decreased GPX1 (Glutathione peroxidase 1), GSTP1 (glutathione S-transferase pi 1), and GSR (glutathione-disulfide reductase) expression and increased GSH (Glutathione) levels, and improved cellular senescence as shown by the markers β-galactosidase, γH2Ax and Klotho-beta.

Conclusions

In conclusion, ALA ameliorated ER stress, oxidative stress, and inflammation in HepG2 cells treated with palmitic and oleic acids, potentially offering therapeutic benefits for NAFLD providing a possible biochemical mechanism underlying ALA beneficial effects.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-024-04880-x.

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Most cited references 68

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Agnieszka Loboda, Milena Damulewicz, Elżbieta Pyza … (2016)

The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

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Cytokines in Inflammatory Disease

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This review aims to briefly discuss a short list of a broad variety of inflammatory cytokines. Numerous studies have implicated that inflammatory cytokines exert important effects with regard to various inflammatory diseases, yet the reports on their specific roles are not always consistent. They can be used as biomarkers to indicate or monitor disease or its progress, and also may serve as clinically applicable parameters for therapies. Yet, their precise role is not always clearly defined. Thus, in this review, we focus on the existing literature dealing with the biology of cytokines interleukin (IL)-6, IL-1, IL-33, tumor necrosis factor-alpha (TNF-α), IL-10, and IL-8. We will briefly focus on the correlations and role of these inflammatory mediators in the genesis of inflammatory impacts (e.g., shock, trauma, immune dysregulation, osteoporosis, and/or critical illness).

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Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

David Ipsen, Jens Lykkesfeldt, Pernille Tveden-Nyborg (2018)

Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.

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Author and article information

Contributors

Giovanni Li Volti:

ORCID: http://orcid.org/0000-0002-8678-2183

livolti@unict.it

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 20 January 2024

Publication date PMC-release: 20 January 2024

Publication date Collection: 2024

Volume: 22

Electronic Location Identifier: 82

Affiliations

[1 ]Department of Biomedical and Biotechnological Sciences, University of Catania, ( https://ror.org/03a64bh57) 95123 Catania, Italy

[2 ]Hospital Pharmacy Unit, Ospedale Cannizzaro, 95125 Catania, Italy

[3 ]Pharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, ( https://ror.org/02f81g417) 11451 Riyadh, Saudi Arabia

[4 ]Division of Gastroenterology, Ospedale Di Acireale, Azienda Sanitaria Provinciale Di Catania, Catania, Italy

[5 ]U.O.S. Laboratory Analysis, Maggiore “Nino Baglieri” Hospital - ASP Ragusa, 97015 Modica (RG), Italy

[6 ]GRID grid.512346.7, UniCamillus-Saint Camillus International University of Health Sciences, ; Via Di Sant’Alessandro 8, 00131 Rome, Italy

[7 ]Department of Experimental and Clinical Medicine, Magna Graecia University, ( https://ror.org/0530bdk91) Catanzaro, Italy

Author information

Giovanni Li Volti http://orcid.org/0000-0002-8678-2183

Article

Publisher ID: 4880

DOI: 10.1186/s12967-024-04880-x

PMC ID: 10799515

PubMed ID: 38245790

SO-VID: 01400457-3903-47d1-8e7e-57474a7bb33a

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 4 December 2023

Date accepted : 10 January 2024

Funding

Funded by: University of catania

Award ID: PIACERI 2020-2022 IMYTRA

Award Recipient : Giovanni Li Volti

Funded by: King Saud University, Riyadh, Saudi Arabia

Award ID: RSP2024R261

Award Recipient : Amer M. Alanazi

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ScienceOpen disciplines: Medicine

Keywords: non-alcoholic fatty liver disease,mitochondrial dysfunction,unfolded protein re-sponse,oxidative stress

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ScienceOpen disciplines: Medicine

Keywords: non-alcoholic fatty liver disease, mitochondrial dysfunction, unfolded protein re-sponse, oxidative stress

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(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease

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Abstract

Background

Results

Conclusions

Graphical Abstract

Supplementary Information

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Most cited references 68

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

Cytokines in Inflammatory Disease

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

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