From Mallory to Mallory-Denk bodies: what, how and why?
Frank B. Mallory described cytoplasmic hyaline inclusions in hepatocytes of patients with alcoholic hepatitis in 1911. These inclusions became known as Mallory bodies (MBs) and have since been associated with a variety of other liver diseases including non-alcoholic fatty liver disease. Helmut Denk and colleagues described the first animal model of MBs in 1975 that involves feeding mice griseofulvin. Since then, mouse models have been instrumental in helping understand the pathogenesis of MBs. Given the tremendous contributions made by Denk to the field, we propose renaming MBs as Mallory-Denk bodies (MDBs). The major constituents of MDBs include keratins 8 and 18 (K8/18), ubiquitin, and p62. The relevant proteins and cellular processes that contribute to MDB formation and accumulation include the type of chronic stress, the extent of stress-induced protein misfolding and consequent proteasome overload, a K8-greater-than-K18 ratio, transamidation of K8 and other proteins, presence of p62 and autophagy. Although it remains unclear whether MDBs serve a bystander, protective or injury promoting function, they do serve an important role as histological and potential progression markers in several liver diseases.
Zatloukal
Kurt
K
Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria.
French
Samuel W
SW
Stumptner
Cornelia
C
Strnad
Pavel
P
Harada
Masaru
M
Toivola
Diana M
DM
Cadrin
Monique
M
Omary
M Bishr
MB
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C027596:Mallory body protein, human; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D007633:Keratins