title: Epiplakin attenuates experimental mouse liver injury by chaperoning keratin reorganization.
abstract: OBJECTIVE
  Epiplakin is a member of the plakin protein family and exclusively expressed in epithelial tissues where it binds to keratins. Epiplakin-deficient (Eppk1(-/-)) mice displayed no obvious spontaneous phenotype, but their keratinocytes showed a faster keratin network breakdown in response to stress. The role of epiplakin in the stressed liver remained to be elucidated.
  
  
  METHODS
  Wild-type (WT) and Eppk1(-/-) mice were subjected to common bile duct ligation (CBDL) or fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet. The importance of epiplakin during keratin reorganization was assessed in primary hepatocytes.
  
  
  RESULTS
  Our experiments revealed that epiplakin is expressed in hepatocytes and cholangiocytes, and binds to keratin 8 (K8) and K18 via multiple domains. In several liver stress models epiplakin and K8 genes displayed identical expression patterns and transgenic K8 overexpression resulted in elevated hepatic epiplakin levels. After CBDL and DDC treatment, Eppk1(-/-) mice developed a more pronounced liver injury and their livers contained larger amounts of hepatocellular keratin granules, indicating impaired disease-induced keratin network reorganization. In line with these findings, primary Eppk1(-/-) hepatocytes showed increased formation of keratin aggregates after treatment with the phosphatase inhibitor okadaic acid, a phenotype which was rescued by the chemical chaperone trimethylamine N-oxide (TMAO). Finally, transfection experiments revealed that Eppk1(-/-) primary hepatocytes were less able to tolerate forced K8 overexpression and that TMAO treatment rescued this phenotype.
  
  
  CONCLUSIONS
  Our data indicate that epiplakin plays a protective role during experimental liver injuries by chaperoning disease-induced keratin reorganization.
authors.affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Szabo
authors.affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Karl L
authors.initials: KL
authors.lastname: Wögenstein
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Österreicher
authors.affiliation: Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany.
authors.forename: Nurdan
authors.initials: N
authors.lastname: Guldiken
authors.affiliation: Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Carina
authors.initials: C
authors.lastname: Doler
authors.affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
authors.affiliation: Division of Nephrology and Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria. Electronic address: peter.fuchs@univie.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates; D059748:Proteolysis; D013312:Stress, Physiological; D015854:Up-Regulation
chemical_list: D001324:Autoantigens; D053538:Keratin-18; D053533:Keratin-8; C486595:Krt8 protein, mouse; D008744:Methylamines; D018832:Molecular Chaperones; D066329:Protein Aggregates; C426678:epiplakin; C005855:trimethyloxamine
keywords: Chaperone; Common bile duct ligation; DDC; Keratin aggregates; Plakins