Keratin 8 overexpression promotes mouse Mallory body formation.
Keratins 8 and 18 (K8/18) are major constituents of Mallory bodies (MBs), which are hepatocyte cytoplasmic inclusions seen in several liver diseases. K18-null but not K8-null or heterozygous mice form MBs, which indicates that K8 is important for MB formation. Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression. We used transgenic mice that overexpress K8, K18, or K8/18 to test the importance of K8 and/or K18 in MB formation. MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Livers of young K8 or K8/K18 overexpressors had no histological abnormalities despite increased keratin protein and phosphorylation. In aging mice, only K8-overexpressing livers spontaneously developed small "pre-MB" aggregates. Only K8-overexpressing young mice are highly susceptible to MB formation after short-term DDC feeding. Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation. K8 overexpression is sufficient to form pre-MB and primes animals to accumulate MBs upon DDC challenge, which may help explain MB formation in human liver diseases.
Nakamichi
Ikuo
I
Department of Medicine, Stanford University, and Veterans Affairs Palo Alto Health Care System, CA 94305, USA.
Toivola
Diana M
DM
Strnad
Pavel
P
Michie
Sara A
SA
Oshima
Robert G
RG
Baribault
Hélène
H
Omary
M Bishr
MB
D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000648:ultrastructure*; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure*; D053538:Keratin-18; D053533:Keratin-8; D007633:Keratins / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
C488421:KRT18 protein, human; D053538:Keratin-18; D053533:Keratin-8; C486595:Krt8 protein, mouse; C488922:Mallory body protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D007633:Keratins