Imperial College London
Alternate

DrLauraMartinez Gili

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Research Fellow
 
 
 
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Contact

 

l.martinez-gili Website

 
 
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Location

 

Queen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Baulies:2015:10.1038/srep18017,
author = {Baulies, A and Ribas, V and Núñez, S and Torres, S and Alarcón-Vila, C and Martínez, L and Suda, J and Ybanez, MD and Kaplowitz, N and García-Ruiz, C and Fernández-Checa, JC},
doi = {10.1038/srep18017},
journal = {Scientific Reports},
title = {Lysosomal cholesterol accumulation sensitizes to acetaminophen hepatotoxicity by impairing mitophagy.},
url = {http://dx.doi.org/10.1038/srep18017},
volume = {5},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase)(-/-) mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase(+/+) littermates. ASMase(-/-) hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase(+/+) hepatocytes caused by U18666A reproduces the susceptibility of ASMase(-/-) hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase(-/-) mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury.
AU  - Baulies,A
AU  - Ribas,V
AU  - Núñez,S
AU  - Torres,S
AU  - Alarcón-Vila,C
AU  - Martínez,L
AU  - Suda,J
AU  - Ybanez,MD
AU  - Kaplowitz,N
AU  - García-Ruiz,C
AU  - Fernández-Checa,JC
DO  - 10.1038/srep18017
PY  - 2015///
SN  - 2045-2322
TI  - Lysosomal cholesterol accumulation sensitizes to acetaminophen hepatotoxicity by impairing mitophagy.
T2  - Scientific Reports
UR  - http://dx.doi.org/10.1038/srep18017
UR  - http://www.ncbi.nlm.nih.gov/pubmed/26657973
UR  - http://hdl.handle.net/10044/1/43290
VL  - 5
ER  -
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