Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form Mallory bodies

Am J Pathol. 2000 Apr;156(4):1263-74. doi: 10.1016/S0002-9440(10)64997-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Ducts / physiology
  • Chemical and Drug Induced Liver Injury
  • Cytoplasm / physiology*
  • Cytoplasm / ultrastructure
  • Cytoskeleton / ultrastructure
  • Dicarbethoxydihydrocollidine
  • Epithelium / physiology
  • Keratin-7
  • Keratins / genetics
  • Keratins / metabolism*
  • Keratins / physiology*
  • Liver / cytology
  • Liver / pathology
  • Liver / physiology*
  • Liver Diseases / pathology
  • Liver Diseases / prevention & control*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout / genetics


  • Keratin-7
  • Krt7 protein, mouse
  • Dicarbethoxydihydrocollidine
  • Keratins