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10.1038/srep18017 http://scihub22266oqcxt.onion/10.1038/srep18017 C4676017!4676017 !26657973     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26657973 &cmd=llinks): Failed to open stream: HTTP request failed! 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Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy |pdf=|usr=}}{{26657973 }} gab.com Text Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy JO: Sci Rep http://www.kidney.de/pget.php?&tw=1&pmid=26657973 #FOAvip 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 ?-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. Twit Text FOAVip Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy ????Sci Rep http://www.kidney.de/pget.php?&tw=1&pmid=26657973 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26657973 #FOAvip English Wikipedia <ref>{{Cite pmid|26657973 }}</ref> Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy #MMPMID26657973 Baulies A ; Ribas V ; Núñez S ; Torres S ; Alarcón-Vila C ; Martínez L ; Suda J ; Ybanez MD ; Kaplowitz N ; García-Ruiz C ; Fernández-Checa JC Sci Rep 2015[Dec]; 5 (ä): 18017 PMID26657973 show ga 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 ?-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. |*Drug Resistance/genetics [MESH] |Acetaminophen/metabolism/*pharmacology/toxicity [MESH] |Animals [MESH] |Chemical and Drug Induced Liver Injury/genetics/metabolism/pathology [MESH] |Cholesterol/*metabolism [MESH] |Glutathione/metabolism [MESH] |Hepatocytes/*drug effects/*metabolism [MESH] |Humans [MESH] |JNK Mitogen-Activated Protein Kinases/metabolism [MESH] |Lysosomes/*metabolism [MESH] |Mice [MESH] |Mice, Knockout [MESH] |Mitochondria, Liver/drug effects/metabolism [MESH] |Mitophagy/*drug effects [MESH] |Phagosomes [MESH]Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatot(epmc).pdf DeepDyve Pubget Overpricing