ArticleScientific reports2015
Lysosomal Cholesterol Accumulation Sensitizes To Acetaminophen Hepatotoxicity by Impairing Mitophagy.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 56 citations in OpenAlex.
- Animal models accurately representing acute liver failure (Review).International journal of molecular medicine · 2026Review
- Preoperative Beta-Hydroxy-Beta-Methyl-Butyrate Supplementation Reduces Mitochondrial Dynamics Proteins and Preserves Hepatic Mitochondrial Function After Partial Hepatectomy in Mice.Acta physiologica (Oxford, England) · 2026Article
- Roles of the Keap1/Nrf2 pathway and mitophagy in liver diseases.Journal of Zhejiang University. Science. B · 2025Review
- Mechanism and regulation of mitophagy in liver diseases: a review.Frontiers in cell and developmental biology · 2025Review
- The relevance of acid sphingomyelinase as a potential target for therapeutic intervention in hepatic disorders: current scenario and anticipated trends.Archives of toxicology · 2023Review
- Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition of GSK3β phosphorylation and mitochondrial translocation.Experimental & molecular medicine · 2023Article
- Article
- Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury.Cell biology and toxicology · 2022Article
- Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation.Molecular oncology · 2022Article
- Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218.Acta pharmaceutica Sinica. B · 2021Article
- Mitochondrial stress response in drug-induced liver injury.Molecular biology reports · 2021Review
- Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation.Redox biology · 2021Article
- Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice.Antioxidants (Basel, Switzerland) · 2021Review
- Autophagy in liver diseases.World journal of hepatology · 2021Review
- Cell Death in Liver Diseases: A Review.International journal of molecular sciences · 2020Review
- Sphingomyelinases and Liver Diseases.Biomolecules · 2020Review
- Diclofenac impairs autophagic flux via oxidative stress and lysosomal dysfunction: Implications for hepatotoxicity.Redox biology · 2020Article
- A mitochondrial journey through acetaminophen hepatotoxicity.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2020Review
- Review
- Multiple Roles of 25-Hydroxycholesterol in Lipid Metabolism, Antivirus Process, Inflammatory Response, and Cell Survival.Oxidative medicine and cellular longevity · 2020Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.