Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease
Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38165-6 |
| _version_ | 1797817928385560576 |
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| author | Jialiu Zeng Rebeca Acin-Perez Essam A. Assali Andrew Martin Alexandra J. Brownstein Anton Petcherski Lucía Fernández-del-Rio Ruiqing Xiao Chih Hung Lo Michaël Shum Marc Liesa Xue Han Orian S. Shirihai Mark W. Grinstaff |
| author_facet | Jialiu Zeng Rebeca Acin-Perez Essam A. Assali Andrew Martin Alexandra J. Brownstein Anton Petcherski Lucía Fernández-del-Rio Ruiqing Xiao Chih Hung Lo Michaël Shum Marc Liesa Xue Han Orian S. Shirihai Mark W. Grinstaff |
| author_sort | Jialiu Zeng |
| collection | DOAJ |
| description | Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD. |
| first_indexed | 2024-03-13T09:00:35Z |
| format | Article |
| id | doaj.art-7d8571474b5446d88e1e67b698c99e4f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T09:00:35Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-7d8571474b5446d88e1e67b698c99e4f2023-05-28T11:20:52ZengNature PortfolioNature Communications2041-17232023-05-0114111710.1038/s41467-023-38165-6Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver diseaseJialiu Zeng0Rebeca Acin-Perez1Essam A. Assali2Andrew Martin3Alexandra J. Brownstein4Anton Petcherski5Lucía Fernández-del-Rio6Ruiqing Xiao7Chih Hung Lo8Michaël Shum9Marc Liesa10Xue Han11Orian S. Shirihai12Mark W. Grinstaff13Department of Biomedical Engineering, Boston UniversityDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDepartment of Biomedical Engineering, Boston UniversityDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDepartment of Chemistry, Boston UniversityLee Kong Chian School of Medicine, Nanyang Technological University, SingaporeDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDepartment of Biomedical Engineering, Boston UniversityDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los AngelesDepartment of Biomedical Engineering, Boston UniversityAbstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.https://doi.org/10.1038/s41467-023-38165-6 |
| spellingShingle | Jialiu Zeng Rebeca Acin-Perez Essam A. Assali Andrew Martin Alexandra J. Brownstein Anton Petcherski Lucía Fernández-del-Rio Ruiqing Xiao Chih Hung Lo Michaël Shum Marc Liesa Xue Han Orian S. Shirihai Mark W. Grinstaff Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease Nature Communications |
| title | Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease |
| title_full | Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease |
| title_fullStr | Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease |
| title_full_unstemmed | Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease |
| title_short | Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease |
| title_sort | restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non alcoholic fatty liver disease |
| url | https://doi.org/10.1038/s41467-023-38165-6 |
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