K. Zatloukal et al., Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form mallory bodies, AM J PATH, 156(4), 2000, pp. 1263-1274
Citations number
91
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
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, hepatocyt
es form cytoplasmic protein aggregates (Mallory bodies; MBs) containing cyt
okeratins (CKs) and non-CK components. Here we report that mice lacking the
CK8 gene and hence CK intermediate filaments in hepatocytes, but still exp
ressing the type I partner, ie, the CK18 gene, do not form MBs but suffer f
rom extensive porphyria and progressive toxic Liver damage, leading to the
death of a considerable number of animals (7 of 12 during 12 weeks of intox
ication). 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 a
nd toxic Liver damage are drastically enhanced in the absence of CK8. Our r
esults point to a protective role of CKs in certain types of toxic liver in
jury 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.