(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease
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 r...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-04880-x |
| _version_ | 1797349728559562752 |
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| author | Lucia Longhitano Alfio Distefano Nicolò Musso Paolo Bonacci Laura Orlando Sebastiano Giallongo Daniele Tibullo Simona Denaro Giuseppe Lazzarino Jessica Ferrigno Anna Nicolosi Amer M. Alanazi Federico Salomone Emanuela Tropea Ignazio Alberto Barbagallo Vincenzo Bramanti Giovanni Li Volti Giacomo Lazzarino Daniele Torella Angela Maria Amorini |
| author_facet | Lucia Longhitano Alfio Distefano Nicolò Musso Paolo Bonacci Laura Orlando Sebastiano Giallongo Daniele Tibullo Simona Denaro Giuseppe Lazzarino Jessica Ferrigno Anna Nicolosi Amer M. Alanazi Federico Salomone Emanuela Tropea Ignazio Alberto Barbagallo Vincenzo Bramanti Giovanni Li Volti Giacomo Lazzarino Daniele Torella Angela Maria Amorini |
| author_sort | Lucia Longhitano |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-03-08T12:34:35Z |
| format | Article |
| id | doaj.art-9570686faf184a6198d99cf59b361aaf |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T12:34:35Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-9570686faf184a6198d99cf59b361aaf2024-01-21T12:33:18ZengBMCJournal of Translational Medicine1479-58762024-01-0122111810.1186/s12967-024-04880-x(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver diseaseLucia Longhitano0Alfio Distefano1Nicolò Musso2Paolo Bonacci3Laura Orlando4Sebastiano Giallongo5Daniele Tibullo6Simona Denaro7Giuseppe Lazzarino8Jessica Ferrigno9Anna Nicolosi10Amer M. Alanazi11Federico Salomone12Emanuela Tropea13Ignazio Alberto Barbagallo14Vincenzo Bramanti15Giovanni Li Volti16Giacomo Lazzarino17Daniele Torella18Angela Maria Amorini19Department of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaHospital Pharmacy UnitPharmaceutical Biotechnology Laboratory, Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud UniversityDivision of Gastroenterology, Ospedale Di Acireale, Azienda Sanitaria Provinciale Di CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaDepartment of Biomedical and Biotechnological Sciences, University of CataniaU.O.S. Laboratory Analysis, Maggiore “Nino Baglieri” Hospital - ASP RagusaDepartment of Biomedical and Biotechnological Sciences, University of CataniaUniCamillus-Saint Camillus International University of Health SciencesDepartment of Experimental and Clinical Medicine, Magna Graecia UniversityDepartment of Biomedical and Biotechnological Sciences, University of CataniaAbstract 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 Abstracthttps://doi.org/10.1186/s12967-024-04880-xNon-alcoholic fatty liver diseaseMitochondrial dysfunctionUnfolded protein re-sponseOxidative stress |
| spellingShingle | Lucia Longhitano Alfio Distefano Nicolò Musso Paolo Bonacci Laura Orlando Sebastiano Giallongo Daniele Tibullo Simona Denaro Giuseppe Lazzarino Jessica Ferrigno Anna Nicolosi Amer M. Alanazi Federico Salomone Emanuela Tropea Ignazio Alberto Barbagallo Vincenzo Bramanti Giovanni Li Volti Giacomo Lazzarino Daniele Torella Angela Maria Amorini (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease Journal of Translational Medicine Non-alcoholic fatty liver disease Mitochondrial dysfunction Unfolded protein re-sponse Oxidative stress |
| title | (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease |
| title_full | (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease |
| title_fullStr | (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease |
| title_full_unstemmed | (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease |
| title_short | (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease |
| title_sort | lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non alcoholic fatty liver disease |
| topic | Non-alcoholic fatty liver disease Mitochondrial dysfunction Unfolded protein re-sponse Oxidative stress |
| url | https://doi.org/10.1186/s12967-024-04880-x |
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