ArticleHepatology (Baltimore, Md.)2015
Human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with c-jun amino-terminal kinase activation and protein adduct formation.
Article in Hepatology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Alpha-1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid-Inducible Manner.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Keratin8 Deficiency Aggravates Retinal Ganglion Cell Damage Under Acute Ocular Hypertension.Investigative ophthalmology & visual science · 2023Article
- Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis.International journal of molecular sciences · 2021Article
- Cytoskeleton and Associated Proteins: Pleiotropic JNK Substrates and Regulators.International journal of molecular sciences · 2021Review
- Revealing the Roles of Keratin 8/18-Associated Signaling Proteins Involved in the Development of Hepatocellular Carcinoma.International journal of molecular sciences · 2021Review
- Leukamenin E Induces K8/18 Phosphorylation and Blocks the Assembly of Keratin Filament Networks Through ERK Activation.International journal of molecular sciences · 2020Article
- The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8.OncoTargets and therapy · 2020Article
- Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy.Cell death & disease · 2019Article
- Liver disease-associated keratin 8 and 18 mutations modulate keratin acetylation and methylation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- The role of keratins in the digestive system: lessons from transgenic mouse models.Histochemistry and cell biology · 2018Review
- Intermediate filament proteins of digestive organs: physiology and pathophysiology.American journal of physiology. Gastrointestinal and liver physiology · 2017Review
- Prevalence of genetic variants of keratins 8 and 18 in patients with drug-induced liver injury.BMC medicine · 2015Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
unlabelledKeratins 8 and 18 (K8/K18) are the intermediate filaments proteins of simple-type digestive epithelia and provide important cytoprotective function. K8/K18 variants predispose humans to chronic liver disease progression and poor outcomes in acute acetaminophen (APAP)-related liver failure. Given that K8 G62C and R341H/R341C are common K8 variants in European and North American populations, we studied their biological significance using transgenic mice. Mice that overexpress the human K8 variants, R341H or R341C, were generated and used together with previously described mice that overexpress wild-type K8 or K8 G62C. Mice were injected with 600 mg/kg of APAP or underwent bile duct ligation (BDL). Livers were evaluated by microarray analysis, quantitative real-time polymerase chain reaction, immunoblotting, histological and immunological staining, and biochemical assays. Under basal conditions, the K8 G62C/R341H/R341C variant-expressing mice did not show an obvious liver phenotype or altered keratin filament distribution, whereas K8 G62C/R341C animals had aberrant disulphide cross-linked keratins. Animals carrying the K8 variants displayed limited gene expression changes, but had lower nicotinamide N-methyl transferase (NNMT) levels and were predisposed to APAP-induced hepatotoxicity. NNMT represents a novel K8/K18-associated protein that becomes up-regulated after K8/K18 transfection. The more pronounced liver damage was accompanied by increased and prolonged JNK activation; elevated APAP protein adducts; K8 hyperphosphorylation at S74/S432 with enhanced keratin solubility; and prominent pericentral keratin network disruption. No differences in APAP serum levels, glutathione, or adenosine triphosphate levels were noted. BDL resulted in similar liver injury and biliary fibrosis in all mouse genotypes.
conclusionExpression of human K8 variants G62C, R341H, or R341C in mice predisposes to acute APAP hepatotoxicity, thereby providing direct evidence for the importance of these variants in human acute liver failure.
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