| Keratins let liver live: Mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies. | |
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MedLine Citation:
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PMID: 17969036 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Keratin polypeptides 8 and 18 (K8/K18) are the cytoskeletal intermediate filament proteins of hepatocytes while K8/K18/K19 are the keratins of hepatobiliary ductal cells. Hepatocyte K8/K18 are highly abundant and behave as stress proteins with injury-inducible expression. Human association studies show that K8/K18 germline heterozygous mutations predispose to end-stage liver disease of multiple etiologies ( approximately 3 fold increased risk), and to liver disease progression in patients with chronic hepatitis C infection. These findings are supported by extensive transgenic mouse and ex vivo primary hepatocyte culture studies showing that K8 or K18 mutations predispose the liver to acute or subacute injury and promote apoptosis and fibrosis. Mutation-associated predisposition to liver injury is likely related to mechanical and nonmechanical keratin functions including maintenance of cell integrity, protection from apoptosis and oxidative injury, serving as a phosphate sponge, regulation of mitochondrial organization/function and protein targeting. These functions are altered by mutation-induced changes in keratin phosphorylation, solubility and filament organization/reorganization. Keratins are also the major constituents of Mallory-Denk bodies (MDBs). A toxin-induced K8>K18 ratio, and keratin crosslinking by transglutaminase-2 play essential roles in MDB formation. Furthermore, intracellular or cell-released K18 fragments, generated by caspase-mediated proteolysis during apoptosis serve as markers of liver injury. Therefore, K8 and K18 are cytoprotective stress proteins that play a central role in guarding hepatocytes from apoptosis. Keratin involvement in liver disease is multi-faceted and includes modulating disease progression upon mutation, formation of MDBs in response to unique forms of injury, and serving as markers of epithelial cell death. |
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Authors:
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Nam-On Ku; Pavel Strnad; Bi-Hui Zhong; Guo-Zhong Tao; M Bishr Omary |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Review |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 46 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2007 Nov |
Date Detail:
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Created Date: 2007-11-05 Completed Date: 2007-12-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1639-49 Citation Subset: IM |
Affiliation:
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Department of Medicine, Palo Alto VA Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Biological Markers
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blood Disease Progression Genetic Predisposition to Disease Hepatocytes / physiology Humans Keratin-18 / genetics, metabolism, physiology* Keratin-8 / genetics, metabolism, physiology* Liver / pathology Liver Diseases / genetics, pathology, physiopathology* Mutation |
| Grant Support | |
ID/Acronym/Agency:
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DK47918/DK/NIDDK NIH HHS; DK52951/DK/NIDDK NIH HHS; DK56339/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Biological Markers; 0/Keratin-18; 0/Keratin-8 |
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