ArticleHepatology (Baltimore, Md.)2012
Oxidative stress, Nrf2 and keratin up-regulation associate with Mallory-Denk body formation in mouse erythropoietic protoporphyria.
Article in Hepatology (Baltimore, Md.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Cytochrome P450 as possible link between Mallory-Denk body formation in DDC-intoxicated mouse liver and human steatohepatitis.Virchows Archiv : an international journal of pathology · 2026Article
- Role of SQSTM1/p62 in regulating Mallory-Denk body in alcohol-associated liver disease.eGastroenterology · 2025Article
- Mallory-Denk bodies and hepatocellular senescence: a causal relationship?Virchows Archiv : an international journal of pathology · 2024Article
- Impaired hepatic autophagy exacerbates hepatotoxin induced liver injury.Cell death discovery · 2023Article
- Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis.International journal of molecular sciences · 2021Article
- Article
- A Novel Mechanism for NF-κB-activation via IκB-aggregation: Implications for Hepatic Mallory-Denk-Body Induced Inflammation.Molecular & cellular proteomics : MCP · 2020Article
- Nrf2 Ameliorates DDC-Induced Sclerosing Cholangitis and Biliary Fibrosis and Improves the Regenerative Capacity of the Liver.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury.Journal of hepatology · 2019Article
- Oxygen and Conformation Dependent Protein Oxidation and Aggregation by Porphyrins in Hepatocytes and Light-Exposed Cells.Cellular and molecular gastroenterology and hepatology · 2019Article
- Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury.Cellular and molecular gastroenterology and hepatology · 2019Review
- Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress.British journal of pharmacology · 2018Article
- The PPARα Agonist Fenofibrate Prevents Formation of Protein Aggregates (Mallory-Denk bodies) in a Murine Model of Steatohepatitis-like Hepatotoxicity.Scientific reports · 2018Article
- Keratin 18-deficiency results in steatohepatitis and liver tumors in old mice: A model of steatohepatitis-associated liver carcinogenesis.Oncotarget · 2016Article
- Chronic Treatment with Isoniazid Causes Protoporphyrin IX Accumulation in Mouse Liver.Chemical research in toxicology · 2016Article
- A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- p62/Sequestosome-1 Is Indispensable for Maturation and Stabilization of Mallory-Denk Bodies.PloS one · 2016Article
- A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.The Journal of cell biology · 2015Article
- Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1.Science signaling · 2015Article
- Lamin aggregation is an early sensor of porphyria-induced liver injury.Journal of cell science · 2013Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledMallory-Denk bodies (MDBs) are hepatocyte inclusions commonly seen in steatohepatitis. They are induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 12 weeks, which also causes porphyrin accumulation. Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase (fch), and a fraction of EPP patients develop liver disease that is phenocopied in Fech(m1Pas) mutant (fch/fch) mice, which have an inactivating fch mutation. fch/fch mice develop spontaneous MDBs, but the molecular factors involved in their formation and whether they relate to DDC-induced MDBs are unknown. We tested the hypothesis that fch mutation creates a molecular milieu that mimics experimental drug-induced MDBs. In 13- and 20-week-old fch/fch mice, serum alkaline phosphatase, alanine aminotransferase, and bile acids were increased. The 13-week-old fch/fch mice did not develop histologically evident MDBs but manifested biochemical alterations required for MDB formation, including increased transglutaminase-2 and keratin overexpression, with a greater keratin 8 (K8)-to-keratin 18 (K18) ratio, which are critical for drug-induced MDB formation. In 20-week-old fch/fch mice, spontaneous MDBs were readily detected histologically and biochemically. Short-term (3-week) DDC feeding markedly induced MDB formation in 20-week-old fch/fch mice. Under basal conditions, old fch/fch mice had significant alterations in mitochondrial oxidative-stress markers, including increased protein oxidation, decreased proteasomal activity, reduced adenosine triphosphate content, and Nrf2 (redox sensitive transcription factor) up-regulation. Nrf2 knockdown in HepG2 cells down-regulated K8, but not K18.
conclusionFch/fch mice develop age-associated spontaneous MDBs, with a marked propensity for rapid MDB formation upon exposure to DDC, and therefore provide a genetic model for MDB formation. Inclusion formation in the fch/fch mice involves oxidative stress which, together with Nrf2-mediated increase in K8, promotes MDB formation.
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