Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy

被引:41
作者
Baulies, Anna [1 ,2 ,3 ]
Ribas, Vicent [1 ,2 ,3 ]
Nunez, Susana [1 ,2 ,3 ]
Torres, Sandra [1 ,2 ,3 ]
Alarcon-Vila, Cristina [1 ,2 ,3 ]
Martinez, Laura [1 ,2 ,3 ]
Suda, Jo [4 ]
Ybanez, Maria D. [4 ]
Kaplowitz, Neil [4 ]
Garcia-Ruiz, Carmen [1 ,2 ,3 ,5 ]
Fernandez-Checa, Jose C. [1 ,2 ,3 ,5 ]
机构
[1] CSIC, Inst Invest Biomed Barcelona, Dept Cell Death & Proliferat, Barcelona, Spain
[2] Liver Unit Hosp Clin IDIBAPS, Barcelona, Spain
[3] Ctr Invest Biomed Red CIBERehd, Barcelona, Spain
[4] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Res Ctr Liver Dis, Los Angeles, CA 90089 USA
[5] Univ So Calif, Keck Sch Med, Res Ctr Alcohol Liver & Pancreat Dis & Cirrhosis, Los Angeles, CA 90089 USA
来源
SCIENTIFIC REPORTS | 2015年 / 5卷
关键词
MITOCHONDRIAL PERMEABILITY TRANSITION; SPHINGOMYELINASE-CERAMIDE SYSTEM; ACID SPHINGOMYELINASE; INDUCED NECROSIS; PROTECTIVE ROLE; AUTOPHAGY; GLUTATHIONE; MECHANISMS; DEFICIENT; MOUSE;
D O I
10.1038/srep18017
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-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.
引用
收藏
页数:15
相关论文
共 55 条
[1]   Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation [J].
Appelqvist, Hanna ;
Nilsson, Cathrine ;
Garner, Brett ;
Brown, Andrew J. ;
Kagedal, Katarina ;
Ollinger, Karin .
AMERICAN JOURNAL OF PATHOLOGY, 2011, 178 (02) :629-639
[2]   Acute liver failure [J].
Bernal, William ;
Auzinger, Georg ;
Dhawan, Anil ;
Wendon, Julia .
LANCET, 2010, 376 (9736) :190-201
[3]  
DECAPRIO J, 1992, J LIPID RES, V33, P441
[4]   Mitophagy: mechanisms, pathophysiological roles, and analysis [J].
Ding, Wen-Xing ;
Yin, Xiao-Ming .
BIOLOGICAL CHEMISTRY, 2012, 393 (07) :547-564
[5]   Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in BLOC-3 [J].
Falcón-Pérez, JM ;
Nazarian, R ;
Sabatti, C ;
Dell'Angelica, EC .
JOURNAL OF CELL SCIENCE, 2005, 118 (22) :5243-5255
[6]   ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis [J].
Fucho, Raquel ;
Martinez, Laura ;
Baulies, Anna ;
Torres, Sandra ;
Tarrats, Nuria ;
Fernandez, Anna ;
Ribas, Vicente ;
Astudillo, Alma M. ;
Balsinde, Jesus ;
Garcia-Roves, Pablo ;
Elena, Montserrat ;
Bergheim, Ina ;
Lotersztajn, Sophie ;
Trautwein, Christian ;
Appelqvist, Hanna ;
Paton, Adrienne W. ;
Paton, James C. ;
Czaja, Mark J. ;
Kaplowitz, Neil ;
Fernandez-Checa, Jose C. ;
Garcia-Ruiz, Carmen .
JOURNAL OF HEPATOLOGY, 2014, 61 (05) :1126-1134
[7]   High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A [J].
Gabande-Rodriguez, E. ;
Boya, P. ;
Labrador, V. ;
Dotti, C. G. ;
Ledesma, M. D. .
CELL DEATH AND DIFFERENTIATION, 2014, 21 (06) :864-875
[8]   Defective TNF-α-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice [J].
García-Ruiz, C ;
Colell, A ;
Marí, M ;
Morales, A ;
Calvo, M ;
Enrich, C ;
Fernández-Checa, JC .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (02) :197-208
[9]   Acid sphingomyelinase-ceramide system in steatohepatitis: A novel target regulating multiple pathways [J].
Garcia-Ruiz, Carmen ;
Mato, Jose M. ;
Vance, Dennis ;
Kaplowitz, Neil ;
Fernandez-Checa, Jose C. .
JOURNAL OF HEPATOLOGY, 2015, 62 (01) :219-233
[10]  
GARCIARUIZ C, 1995, HEPATOLOGY, V21, P207, DOI 10.1016/0270-9139(95)90430-1