ArticleHepatology (Baltimore, Md.)2017
Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin.
Article in Hepatology (Baltimore, Md.), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.The Journal of biological chemistry · 2026Article
- The Alpha-1 Pi*MZ Genotype Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Patients With ACLD.Alimentary pharmacology & therapeutics · 2026Article
- Application of Induced Pluripotent Stem Cells (iPSCs) in Hereditary and Viral Diseases of the Liver: Modeling and Treatment.International journal of molecular sciences · 2025Review
- Article
- An association study ofBiochemistry and biophysics reports · 2025Article
- 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
- Genetic and clinical factors influencing CF-associated liver disease: the impact ofMedicine and pharmacy reports · 2024Article
- HRD1-mediated METTL14 degradation regulates mMolecular cell · 2021Article
- Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum.Progress in molecular and subcellular biology · 2021Article
- Liver Fibrosis-From Mechanisms of Injury to Modulation of Disease.Frontiers in medicine · 2021Review
- CHOP and c-JUN up-regulate the mutant Z αThe Journal of biological chemistry · 2020Article
- Alpha-1 Antitrypsin Deficiency-Mediated Liver Toxicity: Why Do Some Patients Do Poorly? What Do We Know So Far?Chronic obstructive pulmonary diseases (Miami, Fla.) · 2020Review
- Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach.International journal of molecular sciences · 2020Review
- New Therapeutic Targets for Alpha-1 Antitrypsin Deficiency.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2018Article
- Liver: Taking out the JuNK to treat α1-antitrypsin deficiency.Nature reviews. Gastroenterology & hepatology · 2017Article
- Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions.Current pathobiology reports · 2017Review
- Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency.International journal of chronic obstructive pulmonary disease · 2017Article
- ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.PloS one · 2017Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
Alpha1-antitrypsin deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the serine protease inhibitor 1A (SERPINA1) gene leading to a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Alpha1-antitrypsin defciency-related liver disease is therefore caused by a gain-of-function mechanism due to accumulation of the mutant Z alpha1-antitrypsin (ATZ) and is a key example of an disease mechanism induced by protein toxicity. Intracellular retention of ATZ triggers a complex injury cascade including apoptosis and other mechanisms, although several aspects of the disease pathogenesis are still unclear. We show that ATZ induces activation of c-Jun N-terminal kinase (JNK) and c-Jun and that genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c-Jun-mediated SERPINA1 gene expression. JNK activation was confirmed in livers of patients homozygous for the Z allele, with severe liver disease requiring hepatic transplantation. Treatment of patient-derived induced pluripotent stem cell-hepatic cells with a JNK inhibitor reduced accumulation of ATZ.
conclusionThese data reveal that JNK is a key pathway in the disease pathogenesis and add new therapeutic entry points for liver disease caused by ATZ. (Hepatology 2017;65:1865-1874).
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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.