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High-fat diet triggers Mallory-Denk body formation via misfolding and crosslinking of excess keratin 8.
MedLine Citation:
PMID:  24519272     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated keratins 8/18 (K8/K18). MDBs are characteristic of alcoholic and non-alcoholic steatohepatitis (NASH) and discriminate between the relatively benign simple steatosis and the more aggressive NASH. Given the emerging evidence for a genetic predisposition to MDB formation and NASH development in general, we studied whether high-fat (HF) diet triggers MDB formation and liver injury in susceptible animals. Mice were fed a high-fat (HF) or low-fat (LF) diet plus a co-factor for MDB development, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Additionally, we fed non-transgenic and K8 overexpressing mice (K8tg) with HF diet. The presence of MDB and extent of liver injury was evaluated using biochemical markers, histological staining, and immunofluorescence microscopy. In DDC-fed animals, HF diet resulted in greater liver injury and up-regulation of inflammation-related genes. As a potential mechanism, K8/K18 accumulation and increased ecto-5'-nucleotidase (CD73) levels were noted. In the genetically susceptible K8tg mice, HF diet triggered hepatocellular injury, ballooning, apoptosis, inflammation, and MDB development via (i) decreased expression of the major stress-inducible chaperone Hsp72 with appearance of misfolded keratins; (ii) elevated levels of the transglutaminase 2 (TG2); (iii) increased K8 phosphorylation at S74 with subsequent TG2-mediated crosslinking of phosphorylated K8; and (iv) higher production of the MDB-modifier gene CD73. Conclusion: Our data demonstrate that HF diet triggers aggregate formation and development of liver injury in susceptible individuals via misfolding and crosslinking of excess K8. (Hepatology 2014;).
Authors:
Ozlem Kucukoglu; Nurdan Guldiken; Yu Chen; Valentyn Usachov; Amin El-Heliebi; Johannes Haybaeck; Helmut Denk; Christian Trautwein; Pavel Strnad
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-2-12
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-2-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 American Association for the Study of Liver Diseases.
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