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Title: Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease
Authors: Zeng, Jialiu 
Acin-Perez, Rebeca
Assali, Essam A.
Martin, Andrew
Brownstein, Alexandra J.
Petcherski, Anton
Fernández-del-Rio, Lucía
Xiao, Ruiqing
Lo, Chih Hung
Shum, Michaël
Liesa, Marc
Han, Xue
Shirihai, Orian S.
Grinstaff, Mark W.
Keywords: Science::Medicine
Issue Date: 2023
Source: Zeng, J., Acin-Perez, R., Assali, E. A., Martin, A., Brownstein, A. J., Petcherski, A., Fernández-del-Rio, L., Xiao, R., Lo, C. H., Shum, M., Liesa, M., Han, X., Shirihai, O. S. & Grinstaff, M. W. (2023). Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease. Nature Communications, 14(1), 2573-.
Project: 021229-00001 
Journal: Nature Communications 
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.
ISSN: 2041-1723
DOI: 10.1038/s41467-023-38165-6
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Rights: © The Author(s) 2023. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit licenses/by/4.0/.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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