High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8

Kücükoglu, Özlem; Güldiken, Nurdan; Chen, Yu; Usachov, Valentyn; El‐Heliebi, Amin; Haybaeck, Johannes; Denk, Helmut; Strnad, Pavel

doi:10.1002/hep.27068

Cited by 42 publications

(34 citation statements)

References 44 publications

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“…In the present study, the distribution of MDBs stained positive for ubiquitin was 80% in overlap syndrome, 86% in chronic hepatitis B, and 100% in ASH, NASH, chronic viral hepatitis C, and primary biliary cirrhosis. In another study, Kucukoglu et al (20) illustrated that the effects accountable for reproduced MDB creating can be observed in the high-fat diet fed animals contain remained CD73 degrees, aggregation Keratin 8 (K8)/Keratin 18 (K18), and p62, K8 cross bonding by means of TG2, conversely declined Hsp72 degrees which accommodated with researched misfolding intermediate filament protein.…”

Section: Discussionmentioning

confidence: 98%

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Mallory-Denk bodies: Correlation with steatosis, severity, zonal distribution, and identification with ubiquitin

Kayaçetin¹,

Başaranoğlu²

2015

Turk J Gastroenterol

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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 with chronic liver disease were included in the current study. Immunohistochemistry analysis was conducted on frozen liver biopsies fixed at room temperature with acetone anti-rabbit antibody to ubiquitin. In addition, histological activity was evaluated by the routine staining of liver biopsy sections with hematoxylin-eosin and periodic staining by acid-Schiff stain, reticulin, Masson trichrome, and iron. The presence of MDBs, steatosis, severity, and the zonal distribution of hepatocyte balloon degeneration were evaluated in every patient. Results: Histopathologic diagnosis were chronic hepatitis B (n=219), alcoholic steatohepatitis (n=23), non-alcoholic steatohepatitis (n=20), chronic hepatitis C (n=20), overlap syndrome (n=10), and primary biliary cirrhosis (n=8). The distribution of MDBs stained positive for ubiquitin was 80% in the overlap syndrome, 86% in chronic hepatitis B, and 100% in alcoholic steatohepatitis, NASH, chronic hepatitis C, and primary biliary cirrhosis. There was a correlation between the severity of steatosis and ubiquitin positivity, particularly in zone 2. A conspicuous correlation existed between the severity of hepatocyte balloon degeneration and ubiquitin positivity. Conclusion: These findings have demonstrated that the observation of MDB together with ubiquitin positivity will be helpful in the evaluation of the models of diagnosis, staging, and therapy in patients with chronic liver disease.

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Section: Discussionmentioning

confidence: 98%

“…As a matter of fact, this is not amazing that in as much as these keratins are stipulated stress-excitable genes raised in various liver disorders (20).…”

Section: Discussionmentioning

confidence: 99%

Mallory-Denk bodies: Correlation with steatosis, severity, zonal distribution, and identification with ubiquitin

Kayaçetin¹,

Başaranoğlu²

2015

Turk J Gastroenterol

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“…The disease may progress to fibrosis, cirrhosis, and end-stage liver disease [23] associated with an increased risk of cardiovascular mortality, type 2 diabetes mellitus and obesity [24][25][26] carrying gender and ethnological variability [27]. The etiology of chronic and acute liver injury has been studied in numerous animal models unraveling the underlying mechanisms specific for the different liver injuries like NASH [28,29], and a1-antitrypsin deficiency [30,31] as prominent examples of chronic liver disease and acetaminophen-(APAP-) induced ALF [32,33] and partial hepatectomy [34] as models for acute liver injury.…”

Section: Introductionmentioning

confidence: 99%

Pathological implications of cadherin zonation in mouse liver

Hempel

Schmitz

Winkler

et al. 2015

Cell. Mol. Life Sci.

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Both acute and chronic liver diseases are associated with ample re-modeling of the liver parenchyma leading to functional impairment, which is thus obviously the cause or the consequence of the disruption of the epithelial integrity. It was, therefore, the aim of this study to investigate the distribution of the adherens junction components E- and N-cadherin, which are important determinants of tissue cohesion. E-cadherin was expressed in periportal but not in perivenous hepatocytes. In contrast, N-cadherin was more enriched towards the perivenous hepatocytes. In agreement, β-catenin, which links both cadherins via α-catenin to the actin cytoskeleton, was expressed ubiquitously. This zonal expression of cadherins was preserved in acute liver injury after treatment with acetaminophen or partial hepatectomy, but disrupted in chronic liver damage like in non-alcoholic steatohepatitis (NASH) or α1-antitrypsin deficiency. Hepatocyte proliferation during acetaminophen-induced liver damage was predominant at the boundary between the damaged perivenous and the intact periportal parenchyma indicating a minor contribution of periportal hepatocytes to liver regeneration. In NASH livers, an oval cell reaction was observed pointing to massive tissue damage coinciding with the gross impairment of hepatocyte proliferation. In the liver parenchyma, metabolic functions are distributed heterogeneously. For example, the expression of phosphoenolpyruvate carboxykinase and E-cadherin overlapped in periportal hepatocytes. Thus, during liver regeneration after acute damage, the intact periportal parenchyma might sustain essential metabolic support like glucose supply or ammonia detoxification. However, disruption of epithelial integrity during chronic challenges may increase susceptibility to metabolic liver diseases such as NASH or vice versa. This might suggest the regulatory integration of tissue cohesion and metabolic functions in the liver.

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“…Supportive of that only a mild keratin‐related phenotype occurs after a high‐fat regimen, is that K8 +/− and K8 +/+ gall bladders and livers responded similarly to a high‐fat lithogenic gallstone‐inducing diet,19 while HFD induced hepatocellular injury in susceptible K8 −/− mice 30. HFD, which has a systemic metabolic effect on the organism, is likely to primarily reflect liver health and not pancreatic islet health.…”

Section: Discussionmentioning

confidence: 99%

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

et al. 2018

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AimDiabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β‐cell keratins, and knockout of K8 (K8−/−) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β‐cell stress and that decreased K8 levels contribute to diabetes susceptibility.MethodsK8‐heterozygous knockout (K8+/−) and wild‐type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)‐induced β‐cell stress and T2D high‐fat diet (HFD).ResultsMurine K8+/− endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β‐cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/− mice after low‐dose/chronic STZ treatment, and STZ causes more β‐cell damage and polyuria in K8+/− compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/−. K8+/− mice showed no major susceptibility risk to HFD compared to K8+/+.ConclusionPartial K8 deficiency reduces β‐cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

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High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8

Cited by 42 publications

References 44 publications

Mallory-Denk bodies: Correlation with steatosis, severity, zonal distribution, and identification with ubiquitin

Mallory-Denk bodies: Correlation with steatosis, severity, zonal distribution, and identification with ubiquitin

Pathological implications of cadherin zonation in mouse liver

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

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