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Mallory-Denk bodies and hepatocellular senescence: a causal relationship?
Helmut Denk1, Peter M Abuja2, Kurt Zatloukal2
1Diagnostic and Research Institute of Pathology, Diagnostic & Research Center of Molecular Biomedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, A-8010, Graz, Austria. helmut.denk@medunigraz.at.
Abstract:
Mallory-Denk bodies (MDBs) are hepatocellular cytoplasmic inclusions, which occur in certain chronic liver diseases, such as alcohol-related (ASH) and metabolic dysfunction-associated (MASH) steatohepatitis, copper toxicosis, some drug-induced liver disorders, chronic cholangiopathies, and liver tumors. Our study focused on the expression of the senescence markers p21WAF1/cip1 and p16INK4a in hepatocytes containing MDBs in steatohepatitis, chronic cholangiopathies with fibrosis or cirrhosis, Wilson's disease, and hepatocellular carcinomas. Cytoplasm and nuclei of MDB-containing hepatocytes as well as MDB inclusions, except those associated with carcinoma cells, were strongly p16-positive, p21-positive, as well as p21-negative nuclei in MDB-containing hepatocytes which were observed whereas MDBs were p21-negative. Expression of the senescence marker p16 suggests that MDB formation reflects an adaptive response to chronic stress resembling senescence with its consequences, i.e., expression of inflammation- and fibrosis-prone secretome. Thus, senescence can be regarded as "double-edged sword" since, on the one hand, it may be an attempt of cellular defense, but, on the other, also causes further and sustained damage by inducing inflammation and fibrosis related to the senescence-associated secretory phenotype and thus progression of chronic liver disease.
Insights
Mallory-Denk bodies (MDBs) in chronic liver disease may indicate cellular senescence. This adaptive response to stress, while protective, can promote inflammation and fibrosis, worsening liver disease progression.
Area of Science:
- Hepatology
- Cellular Biology
- Senescence Research
Background:
- Mallory-Denk bodies (MDBs) are cytoplasmic inclusions found in various chronic liver diseases.
- Their formation is linked to conditions like alcohol-related steatohepatitis (ASH) and metabolic dysfunction-associated steatohepatitis (MASH).
Purpose of the Study:
- To investigate the expression of senescence markers p21WAF1/cip1 and p16INK4a in hepatocytes containing MDBs.
- To understand the role of MDB formation in the context of cellular senescence and liver disease progression.
Main Methods:
- Immunohistochemical analysis of liver tissues from patients with steatohepatitis, chronic cholangiopathies, Wilson's disease, and hepatocellular carcinomas.
- Detection of p16INK4a and p21WAF1/cip1 expression in hepatocytes and MDB inclusions.
Main Results:
- MDB-containing hepatocytes and inclusions (except in carcinomas) showed strong positivity for p16INK4a and p21WAF1/cip1.
- Some MDB-containing hepatocytes exhibited p21-negative nuclei, while MDBs themselves were p21-negative in certain contexts.
- Strong p16INK4a expression suggests MDB formation is linked to a senescence-like adaptive response to chronic stress.
Conclusions:
- MDB formation in chronic liver disease is associated with cellular senescence markers.
- Senescence, triggered by MDBs, acts as a "double-edged sword," potentially offering cellular defense but also driving inflammation and fibrosis via the senescence-associated secretory phenotype.
- This contributes to the progression of chronic liver disease.
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