ReviewMallory bodies revisited
Section snippets
Diseases Associated with MBs
MBs are characteristically associated with alcoholic and non-alcoholic steatohepatitis (NASH), but are also present in benign and malignant hepatocellular neoplasms, and a diversity of metabolic, toxic and chronic cholestatic liver disorders (for review, see 6., 7., 8., 9., 10., 11., 12.). Their appearance is related to alterations of the cytokeratin (CK) intermediate filament (IF) cytoskeleton of hepatocytes 5., 13., 14..
The spectrum of alcoholic liver disease comprises steatosis, alcoholic
Morphology of MBs
MBs are cytoplasmic inclusions in hepatocytes, ranging in size from small granules to large irregular masses (Fig. 1; see ref. 2., 6., for further information). They display a predominantly filamentous ultrastructure consisting of 10–20-nm-thick filaments coated by fuzzy more electron-dense material2,13,21,Fig. 2). According to their ultrastructural appearance, MBs can be classified as type I (bundles of filaments in parallel arrays), type II (randomly oriented filaments) and type III (granular
MB Formation in Animal Models
Animal models are indispensable tools for elucidation of pathogenetic principles involved in human disease, although usually not all features of human disease can be reproduced in a single model. Several animal models for human alcoholic hepatitis and NASH have been designed 2., 19., 20., 22., 23.. In the alcohol-feeding models fatty liver, centrilobular necrosis, inflammation and fibrosis were markedly exaggerated if ethanol was administered together with a diet rich in polyunsaturated fat 22.
MB composition
The first evidence of a relationship between MBs and the CK cytoskeleton was provided by observations that MBs react with CK antibodies and contain polypeptides closely resembling CKs of hepatocytes Fig. 3, Fig. 4. An additional non-CK protein component with a molecular weight between 62–65 kDa has been found in MBs but not in CKs of normal hepatocytesFig. 4,2,13). The predominantly filamentous ultrastructure of MBs together with diminution of hepatocellular cytoplasmic CK-IF immunostaining was
Clues from CK Gene Knockout Mice
New insights into the role of CKs in MB formation and its functional consequences were recently provided by mice in which the gene for CK8 had been disrupted 112., 113., 114.. Since CK8 (type II CK) and CK18 (type I CK) are the only CKs expressed in normal hepatocytes, no CK IF can be formed in the absence of CK8 115., 116. and the remaining type I CK18 is rapidly degraded. Despite lack of a CK8/18 cytoskeleton homozygous CK8 knockout (−/−) knockout FVB/N mice develop normally without liver
The MB: a Cellular Defense Mechanism to Stress-Induced Protein Damage
As revealed by immunohistochemical, electron microscopic and biochemical analyses MBs resemble filamentous aggregates of phosphorylated, partially proteolytically degraded, ubiquitinated and cross-linked CK and non-CK proteins (including proteins with stress protein characteristics) with CK8 as the essential nucleating factor. It has now amply been documented that aggregation and deposition as abnormal inclusion body is the fate of unfolded or misfolded proteins, and one of the ways the cell
References (123)
- et al.
Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance
J Hepatol
(1998) - et al.
Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis
Hepatology
(1997) Alcoholic liver disease: pathobiological aspects
J Hepatol
(1995)- et al.
Cytoskeletal alterations leading to Mallory body formation in livers of mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine
J Hepatol
(1987) - et al.
N-alkylprotoporphyrin IX formation in 3,5-dicarbethoxy-1,4-dihydrocollidine-treated rats. Transfer of the alkyl group from the substrate to the porphyrin
J Biol Chem
(1981) - et al.
Tau as a marker for Alzheimer's disease
Trends Biol Sci
(1993) - et al.
Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent
Am J Pathol
(1999) - et al.
p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck belongs to a new class of ubiquitin-binding proteins
J Biol Chem
(1996) - et al.
Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multi-ubiquitin chain binding protein
FEBS Lett
(1998) - et al.
Immediate early response of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein
FEBS Lett
(1998)