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.
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19 December 2005
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December 19 2005
Keratin 8 overexpression promotes mouse Mallory body formation
Ikuo Nakamichi,
Ikuo Nakamichi
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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Diana M. Toivola,
Diana M. Toivola
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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Pavel Strnad,
Pavel Strnad
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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Sara A. Michie,
Sara A. Michie
2Department of Pathology, Stanford University, Palo Alto, CA 94305
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Robert G. Oshima,
Robert G. Oshima
4The Burnham Institute, La Jolla, CA 92037
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Hélène Baribault,
Hélène Baribault
5Amgen, South San Francisco, CA 94080
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M. Bishr Omary
M. Bishr Omary
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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Ikuo Nakamichi
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
Diana M. Toivola
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
Pavel Strnad
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
Sara A. Michie
2Department of Pathology, Stanford University, Palo Alto, CA 94305
Robert G. Oshima
4The Burnham Institute, La Jolla, CA 92037
Hélène Baribault
5Amgen, South San Francisco, CA 94080
M. Bishr Omary
1Department of Medicine, Stanford University, Palo Alto, CA 94305
3Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
Correspondence to Bishr Omary: [email protected]
I. Nakamichi and D.M. Toivola contributed equally to this paper.
Abbreviations used in this paper: Ab, antibody; ALT, alanine aminotransferase; DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; IF, intermediate filament; MB, Mallory body; WT, wild type.
Received:
July 19 2005
Accepted:
November 11 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 171 (6): 931–937.
Article history
Received:
July 19 2005
Accepted:
November 11 2005
Citation
Ikuo Nakamichi, Diana M. Toivola, Pavel Strnad, Sara A. Michie, Robert G. Oshima, Hélène Baribault, M. Bishr Omary; Keratin 8 overexpression promotes mouse Mallory body formation . J Cell Biol 19 December 2005; 171 (6): 931–937. doi: https://doi.org/10.1083/jcb.200507093
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