Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease

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 () and Mark W. Grinstaff ()
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Jialiu Zeng: Boston University
Rebeca Acin-Perez: University of California, Los Angeles
Essam A. Assali: University of California, Los Angeles
Andrew Martin: Boston University
Alexandra J. Brownstein: University of California, Los Angeles
Anton Petcherski: University of California, Los Angeles
Lucía Fernández-del-Rio: University of California, Los Angeles
Ruiqing Xiao: Boston University
Chih Hung Lo: Nanyang Technological University, Singapore
Michaël Shum: University of California, Los Angeles
Marc Liesa: University of California, Los Angeles
Xue Han: Boston University
Orian S. Shirihai: University of California, Los Angeles
Mark W. Grinstaff: Boston University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38165-6

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