Abstract:Background/Aims: Intermediate filament proteins contain few aggregates as their main component. Among those, Mallory-Denk bodies (MDBs) are by far the best recognized component. To identify the presence of MDBs in individuals having chronic liver disease and to evaluate the correlation among MDBs and steatosis as well as the severity and zonal distribution of hepatocyte balloon degeneration. Tertiary reference hospital. Materials and Methods: Three hundred consecutive liver specimens derived from our patients … Show more
“…According to Brunt et al [ 48 ] grading and staging system of NASH, these experimental groups fall in grade-2 and fibrotic stage-3. The positive correlation between Mallory–Denk bodies and severity of steatosis and hepatitis was reported by Kayaçetin [ 83 ], which supports our histopathological description. In this study, use of atorvastatin showed no protective effect on histological picture of NAFLD in hypercholesterolemic rabbits, but serum transaminases maintained within normal and serum lipids (lipid profile not shown) significantly reduced; this is in line with Hyogo et al [ 63 ], who reported normalisation of serum transaminases, while the histological picture of NASH improved in some patients and got worse in some others due to progression of fibrosis.…”
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide with no curative therapy. The aim of this study was to investigate the hepatoprotective effects of a novel Trihoney against biochemical and histological manifestations of NAFLD in hypercholesterolemic rabbits. Methodology. Forty-eight male New Zealand white (NZW) rabbits were grouped into normal diet (C), normal diet with 0.6 g/kg/day of Trihoney (C + H), 1% cholesterol diet (HCD), 1% cholesterol diet with 0.3 g/kg/day of Trihoney (HCD + H1), 1% cholesterol diet with 0.6 g/kg/day of Trihoney (HCD + H2), and 1% cholesterol diet with 2 mg/kg/day of atorvastatin (HCD + At.). Animals were sacrificed after 12 weeks of treatment. Serum lipids and liver function test (LFT) were measured prior to and at the endpoint of the experiment for total cholesterol (TC), low-density lipoprotein (LDL-c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (T. Bil.). Liver was processed for histopathology study. Liver homogenate was analysed for oxidative stress parameters: superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA). Results. Lipid analysis approved the induction of hypercholesterolemia. A significant elevation (p<0.01) of serum AST and ALT levels showed by the HCD group was compared to C and C + H groups. Trihoney exhibited a significant reduction (p<0.001) of AST and ALT compared to the HCD group. Likewise, AST and ALT reduced significantly in the HCD + At. group (p<0.001). Trihoney supplementation induced significant (p<0.05) enhancement of SOD and GPx activities. Atorvastatin treatment was associated with significant (p<0.05) reduction of SOD and GPx activities in the liver. Trihoney and atorvastatin showed marked (p<0.001) reduction of hepatic lipid peroxidation. Trihoney showed histological protection against progression of NAFLD to nonalcoholic steatohepatitis (NASH). Atorvastatin exhibited no beneficial impact on hepatic architecture. Conclusion. Trihoney was able to maintain normal liver function and showed hepatoprotection against progression of NAFLD to NASH probably through hypocholesterolaemic and antioxidant functions.
“…According to Brunt et al [ 48 ] grading and staging system of NASH, these experimental groups fall in grade-2 and fibrotic stage-3. The positive correlation between Mallory–Denk bodies and severity of steatosis and hepatitis was reported by Kayaçetin [ 83 ], which supports our histopathological description. In this study, use of atorvastatin showed no protective effect on histological picture of NAFLD in hypercholesterolemic rabbits, but serum transaminases maintained within normal and serum lipids (lipid profile not shown) significantly reduced; this is in line with Hyogo et al [ 63 ], who reported normalisation of serum transaminases, while the histological picture of NASH improved in some patients and got worse in some others due to progression of fibrosis.…”
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide with no curative therapy. The aim of this study was to investigate the hepatoprotective effects of a novel Trihoney against biochemical and histological manifestations of NAFLD in hypercholesterolemic rabbits. Methodology. Forty-eight male New Zealand white (NZW) rabbits were grouped into normal diet (C), normal diet with 0.6 g/kg/day of Trihoney (C + H), 1% cholesterol diet (HCD), 1% cholesterol diet with 0.3 g/kg/day of Trihoney (HCD + H1), 1% cholesterol diet with 0.6 g/kg/day of Trihoney (HCD + H2), and 1% cholesterol diet with 2 mg/kg/day of atorvastatin (HCD + At.). Animals were sacrificed after 12 weeks of treatment. Serum lipids and liver function test (LFT) were measured prior to and at the endpoint of the experiment for total cholesterol (TC), low-density lipoprotein (LDL-c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (T. Bil.). Liver was processed for histopathology study. Liver homogenate was analysed for oxidative stress parameters: superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA). Results. Lipid analysis approved the induction of hypercholesterolemia. A significant elevation (p<0.01) of serum AST and ALT levels showed by the HCD group was compared to C and C + H groups. Trihoney exhibited a significant reduction (p<0.001) of AST and ALT compared to the HCD group. Likewise, AST and ALT reduced significantly in the HCD + At. group (p<0.001). Trihoney supplementation induced significant (p<0.05) enhancement of SOD and GPx activities. Atorvastatin treatment was associated with significant (p<0.05) reduction of SOD and GPx activities in the liver. Trihoney and atorvastatin showed marked (p<0.001) reduction of hepatic lipid peroxidation. Trihoney showed histological protection against progression of NAFLD to nonalcoholic steatohepatitis (NASH). Atorvastatin exhibited no beneficial impact on hepatic architecture. Conclusion. Trihoney was able to maintain normal liver function and showed hepatoprotection against progression of NAFLD to NASH probably through hypocholesterolaemic and antioxidant functions.
“…As a consequence, formation of MDBs can be seen not only as “morphological biomarker” associated with cellular stress and aging but also as product of accumulation of misfolded proteins, which in turn may enhance aging-related cellular responses as indicated by the p16 positivity. This establishes a new diagnostic potential of MDBs, particularly because they are independently associated with fibrosis progression and finally liver failure [ 42 – 44 ]. Fig.…”
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.
“…In line with this point of view are recently published data concerning the protective role of the formation of large insoluble aggregates against the cellular oxidative stress 33 . Intriguingly, the TG2 crosslinking activity plays a key role in the formation of Mallory-Denk bodies (MDBs), which are protein aggregates consisting of ubiquitinated keratins characteristic of alcoholic and NASH 34 . The TG2-dependent formation of highly crosslinked MDBs is functional to their elimination via macroautophagy 20 .…”
Non-alcoholic fatty liver disease (NAFLD) is one of the most important liver diseases worldwide. Currently, no effective treatment is available, and NAFLD pathogenesis is incompletely understood. Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose dysregulation is implicated in the pathogenesis of various human diseases. Here we examined the impact of TG2 on NAFLD progression using the high-fat-diet-induced model in both wild-type and TG2-deficient mice. Animals were fed with a standard chow diet or a high-fat diet (42% of the energy from fat) for 16 weeks. Results demonstrated that the absence of a functional enzyme, which causes the impairment of autophagy/mitophagy, leads to worsening of disease progression. Data were confirmed by pharmacological inhibition of TG2 in WT animals. In addition, the analysis of human liver samples from NAFLD patients validated the enzyme’s involvement in the liver fat disease pathogenesis. Our findings strongly suggest that TG2 activation may offer protection in the context of NAFLD, thus representing a novel therapeutic target for tackling the NAFLD progression.
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