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High amount of epsilon-(gamma-glutamyl)lysine cross-links in Mallory bodies
1Laboratory of Molecular Pathology, University of Graz School of Medicine, Austria.
Abstract:
Alcoholic hepatitis, the most severe form of alcoholic liver disease, is associated with inflammation, liver cell necrosis, and the appearance of Mallory bodies (MBs) in hepatocytes. Identical MBs can be experimentally induced in mouse livers by chronic griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. MBs are filamentous cytoplasmic inclusions containing insoluble high molecular weight protein material. Covalent polymerization of intracellular proteins may occur through formation of epsilon-(gamma-glutamyl)lysine cross-links catalyzed by Ca(2+)-dependent transglutaminases. Therefore, isolated experimentally-induced MBs were analyzed for the presence of epsilon-(gamma-glutamyl)lysine bonds. Highly purified MBs contained 19.7 nmole (griseofulvin-induced) and 14.4 nmoles (3,5-diethoxycarbonyl-1,4-dihydrocollidine induced) of isodipeptide linkage, respectively, per mg of protein. These results suggest that transglutaminase-induced cross-linking of proteins plays a major role in MB formation.
Insights
Mallory bodies (MBs) in alcoholic hepatitis result from protein cross-linking. This study found epsilon-(gamma-glutamyl)lysine bonds in experimentally induced MBs, suggesting transglutaminase activity is key to their formation.
Area of Science:
- Hepatology
- Biochemistry
- Cell Biology
Background:
- Alcoholic hepatitis is the most severe form of alcoholic liver disease.
- It is characterized by inflammation, hepatocyte necrosis, and Mallory bodies (MBs).
- MBs are filamentous cytoplasmic inclusions composed of insoluble, high molecular weight proteins.
Purpose of the Study:
- To investigate the role of protein cross-linking in the formation of experimentally induced Mallory bodies.
- To analyze for the presence of epsilon-(gamma-glutamyl)lysine bonds in MBs.
Main Methods:
- Experimental induction of MBs in mouse livers using griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
- Isolation and purification of MBs.
- Quantification of epsilon-(gamma-glutamyl)lysine cross-links in purified MBs.
Main Results:
- Highly purified MBs contained significant amounts of epsilon-(gamma-glutamyl)lysine isodipeptide linkages.
- Griseofulvin-induced MBs had 19.7 nmoles of linkage per mg of protein.
- 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced MBs had 14.4 nmoles of linkage per mg of protein.
Conclusions:
- Transglutaminase-catalyzed protein cross-linking plays a significant role in Mallory body formation.
- The presence of these cross-links provides a molecular explanation for MBs in alcoholic hepatitis.
- This finding may open new avenues for understanding and potentially treating alcoholic liver disease.