ArticleCellular and molecular gastroenterology and hepatology2022
Hydroxynonenal Causes Hepatocyte Death by Disrupting Lysosomal Integrity in Nonalcoholic Steatohepatitis.
Article in Cellular and molecular gastroenterology and hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 24 citations in OpenAlex.
- Mitochondrial vulnerability to aldehydic load and the role mitochondrial aldehyde dehydrogenases.Pharmacological research · 2026Review
- The Mechanism of G Protein-Coupled Receptor Regulation of Ferroptosis in Hepatic Ischemia-Reperfusion Injury.International journal of molecular sciences · 2026Review
- Increasing Life Expectancy with Plant Polyphenols: Lessons from the Mediterranean and Japanese Diets.Molecules (Basel, Switzerland) · 2025Review
- Sucrose but not arsenic induce hepatic steatosis which correlates with calpain-1 inhibition.PloS one · 2025Article
- 4-Hydroxynonenal from Mitochondrial and Dietary Sources Causes Lysosomal Cell Death for Lifestyle-Related Diseases.Nutrients · 2024Review
- Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.Cell death and differentiation · 2024Article
- Emerging role of ferroptosis in metabolic dysfunction-associated steatotic liver disease: revisiting hepatic lipid peroxidation.EBioMedicine · 2024Review
- Article
- Inflammasome activity regulation by PUFA metabolites.Frontiers in immunology · 2024Review
- Cleavage of Hsp70.1 causes lysosomal cell death under stress conditions.Frontiers in molecular biosciences · 2024Review
- Calpain and Cardiometabolic Diseases.International journal of molecular sciences · 2023Review
- Article
- Vegetable Oil-Peroxidation Product 'Hydroxynonenal' Causes Hepatocyte Injury and Steatosis via Hsp70.1 and BHMT Disorders in the Monkey Liver.Nutrients · 2023Article
- Implication of Vegetable Oil-Derived Hydroxynonenal in the Lysosomal Cell Death for Lifestyle-Related Diseases.Nutrients · 2023Review
- Impact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer's disease.Frontiers in aging neuroscience · 2023Review
- Implication of the cooking oil-peroxidation product "hydroxynonenal" for Alzheimer's disease.Frontiers in aging neuroscience · 2023Review
- Hsp70.1 carbonylation induces lysosomal cell death for lifestyle-related diseases.Frontiers in molecular biosciences · 2022Review
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Authors and funding
16 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsThe lipid oxidation is a key factor for damaging hepatocytes and causing cell death. However, the mechanisms underlying hepatocyte death and the role of the most popular lipid peroxidation product 4-hydroxy-2-nonenal (HNE) in nonalcoholic steatohepatitis (NASH) remains unclear.
methodsWe demonstrated using hepatoma cell lines, a NASH mouse model, HNE-treated monkeys, and biopsy specimens from patients with NASH that HNE induced hepatocyte death by disintegrating the lysosomal limiting membrane.
resultsThe degree of HNE deposition in human NASH hepatocytes was more severe in cases with high lobular inflammation, ballooning, and fibrosis scores, and was associated with enlargement of the staining of lysosomes in hepatocytes. In in vitro experiments, HNE activated μ-calpain via G-protein coupled receptor (GPR) 120. The resultant rupture/permeabilization of the lysosomal limiting membrane induced the leakage of cathepsins from lysosomes and hepatocyte death. The blockade of G-protein coupled receptor 120 (GPR120) or μ-calpain expression suppressed lysosomal membrane damage and hepatocyte death by HNE. Alda-1, which activates aldehyde dehydrogenase 2 to degrade HNE, prevented HNE-induced hepatocyte death. Intravenous administration of HNE to monkeys for 6 months resulted in hepatocyte death by a mechanism similar to that of cultured cells. In addition, intraperitoneal administration of Alda-1 to choline-deficient, amino-acid defined treated mice for 8 weeks inhibited HNE deposition, decreased liver inflammation, and disrupted lysosomal membranes in hepatocytes, resulting in improvement of liver fibrosis.
conclusionsThese results provide novel insights into the mechanism of hepatocyte death in NASH and will contribute to the development of new therapeutic strategies for NASH.
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