Avtor/Urednik		Szabo, Sandra; Wögenstein, Karl L.; Österreicher, Christoph H.; Guldiken, Nurdan; Yu, Chen; Doler, Carina; Wiche, Gerhard; Boor, Peter; Haybaeck, Johannes; Strnad, Pavel
Naslov		Epiplakin attenuates experimental mouse liver injury by chaperoning keratin reorganization
Tip		članek
Vol. in št.		Letnik 62, št. 6
Leto izdaje		2015
Obseg		str. 1357-1366
ISSN		0168-8278 - Journal of hepatology
Jezik		eng
Abstrakt		Background & Aims 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. Conclusion Our data indicate that epiplakin plays a protective role during experimental liver injuries by chaperoning disease-induced keratin reorganization.
Proste vsebinske oznake		common bile duct ligation keratin aggregates liver ligacija skupnega žolčnega kanala keratinski agregati jetra