Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form Mallory bodies.
In alcoholic hepatitis, a severe form of alcohol-induced toxic liver injury, as well as in experimental intoxication of mice with the porphyrinogenic drugs griseofulvin and 3,5-diethoxycarbonyl-1, 4-dihydrocollidine, hepatocytes form cytoplasmic protein aggregates (Mallory bodies; MBs) containing cytokeratins (CKs) and non-CK components. Here we report that mice lacking the CK8 gene and hence CK intermediate filaments in hepatocytes, but still expressing the type I partner, ie, the CK18 gene, do not form MBs but suffer from extensive porphyria and progressive toxic liver damage, leading to the death of a considerable number of animals (7 of 12 during 12 weeks of intoxication). Our observations show that 1) in the absence of CK8 as well as in the situation of a relative excess of CK18 over CK8 no MBs are formed; 2) the loss of CK8 is not compensated by other type II CKs; and 3) porphyria and toxic liver damage are drastically enhanced in the absence of CK8. Our results point to a protective role of CKs in certain types of toxic liver injury and suggest that MBs by themselves are not harmful to hepatocytes but may be considered as a product of a novel defense mechanism in hepatocytes.
Zatloukal
K
K
Department of Pathology, University of Graz, Graz, Austria. kurt.zatloukal@kfunigraz.ac.at
Stumptner
C
C
Lehner
M
M
Denk
H
H
Baribault
H
H
Eshkind
L G
LG
Franke
W W
WW
D000818:Animals; D001652:Bile Ducts / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D003593:Cytoplasm / Q000502:physiology* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000648:ultrastructure; D003997:Dicarbethoxydihydrocollidine; D004848:Epithelium / Q000502:physiology; D053552:Keratin-7; D007633:Keratins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics
D053552:Keratin-7; C507496:Krt7 protein, mouse; D003997:Dicarbethoxydihydrocollidine; D007633:Keratins