Gender Dimorphic Formation of Mouse Mallory–Denk Bodies and the Role of Xenobiotic Metabolism and Oxidative Stress

Hanada, Shinichiro; Snider, Natasha T.; Brunt, Elizabeth M.; Hollenberg, Paul F.; Omary, M. Bishr

doi:10.1053/j.gastro.2009.12.055

Cited by 47 publications

(57 citation statements)

References 45 publications

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“…Similarly, the presence of nuclear lamin or cytoplasmic keratin aggregates (not inclusions per se, presumably due to the smaller-sized aggregates as compared to inclusions seen by standard hematoxylin and eosin staining) has been reported in several laminopathies (Dechat et al, 2008;Bertrand et al, 2011;Worman, 2012) and in the setting of epidermal keratin mutation in the Dowling-Meara form of epidermolysis bullosa simplex (Coulombe et al, 1991). Our findings demonstrate for the first time the presence of nuclear lamin aggregates in the absence of lamin mutation but in response to porphyria-mediated liver injury, which also reflects an oxidative form of liver injury (Hanada et al, 2010;Snider et al, 2011). Our findings are not able to distinguish whether lamin aggregation takes place en-route to the nucleus or directly in the nucleus.…”

Section: Lamin-containing Aggregates Form In the Context Of Liver Injurymentioning

confidence: 53%

Lamin aggregation is an early sensor of porphyria-induced liver injury

Singla

Griggs

Kwan

et al. 2013

Journal of Cell Science

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SummaryOxidative liver injury during steatohepatitis results in aggregation and transglutaminase-2 (TG2)-mediated crosslinking of the keratin cytoplasmic intermediate filament proteins (IFs) to form Mallory-Denk body (MDB) inclusions. The effect of liver injury on lamin nuclear IFs is unknown, though lamin mutations in several human diseases result in lamin disorganization and nuclear shape changes. We tested the hypothesis that lamins undergo aggregation during oxidative liver injury using two MDB mouse models: (i) mice fed the porphyrinogenic drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and (ii) mice that harbor a mutation in ferrochelatase (fch), which converts protoporphyrin IX to heme. Dramatic aggregation of lamin A/C and B1 was noted in the livers of both models in association with changes in lamin organization and nuclear shape, as determined by immunostaining and electron microscopy. The lamin aggregates sequester other nuclear proteins including transcription factors and ribosomal and nuclear pore components into high molecular weight complexes, as determined by mass-spectrometry and confirmed biochemically. Lamin aggregate formation is rapid and precedes keratin aggregation in fch livers, and is seen in liver explants of patients with alcoholic cirrhosis. Exposure of cultured cells to DDC, protoporphyrin IX or Nmethyl-protoporphyrin, or incubation of purified lamins with protoporphyrin IX, also results in lamin aggregation. In contrast, lamin aggregation is ameliorated by TG2 inhibition. Therefore, lamin aggregation is an early sensor of porphyria-associated liver injury and might serve to buffer oxidative stress. The nuclear shape and lamin defects associated with porphyria phenocopy the changes seen in laminopathies and could result in transcriptional alterations due to sequestration of nuclear proteins.

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Section: Lamin-containing Aggregates Form In the Context Of Liver Injurymentioning

confidence: 53%

Lamin aggregation is an early sensor of porphyria-induced liver injury

Singla

Griggs

Kwan

et al. 2013

Journal of Cell Science

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“…The formation of cytoplasmic aggregates in this model is relevant, because IFs are major components of intracellular inclusions seen in several human diseases, including the K8/K18-containing Mallory-Denk bodies that are primarily seen in hepatocytes of patients with steatohepatitis and hepatocellular carcinoma, among other liver diseases (33,38). Examination of the livers of DDC-fed mice, which form human Mallory-Denk body-like inclusions (25,38) suggested that there is no significant localization of SUMO within Mallory-Denk bodies. 3 In light of the study by Kaminsky et al (10) and our current results demonstrating that modest sumoylation increases K8 solubility (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the effect of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury (after a 90-day DDC treatment) on sumoylation, the livers of FVB/N female mice were used as described (25). To determine the effect of the phosphatase inhibitor microcystin LR (MLR) on sumoylation, human K18-overexpressing mice (26) were injected with 30 g/kg of MLR intraperitoneally followed by harvesting of the livers after 195 min.…”

Section: Methodsmentioning

confidence: 99%

“…Increased Sumoylation of Insoluble Liver Proteins during Chronic Mouse Liver Injury-Prolonged feeding of mice with a diet containing the porphyrinogenic compound DDC is a commonly used liver injury model because it reflects some of the hallmarks of chronic human liver injury, such as oxidative stress, matrix accumulation, and inflammation (25,33). Notably, chronic treatment of mice with DDC resulted in a significant induction in the hepatic expression of SUMO-1 and SUMO-2/3 isoforms, as assessed by immunoblotting (Fig.…”

Section: Keratins Are Sumoylated In Primary Mouse Hepatocytes and In mentioning

confidence: 99%

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Keratin Hypersumoylation Alters Filament Dynamics and Is a Marker for Human Liver Disease and Keratin Mutation

Snider

Weerasinghe

Iñiguez‐Lluhí³

et al. 2011

Journal of Biological Chemistry

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Keratin polypeptide 8 (K8) associates noncovalently with its partners K18 and/or K19 to form the intermediate filament cytoskeleton of hepatocytes and other simple-type epithelial cells. Human K8, K18, and K19 variants predispose to liver disease, whereas site-specific keratin phosphorylation confers hepatoprotection. Because stress-induced protein phosphorylation regulates sumoylation, we hypothesized that keratins are sumoylated in an injury-dependent manner and that keratin sumoylation is an important regulatory modification. We demonstrate that K8/K18/K19, epidermal keratins, and vimentin are sumoylated in vitro. Upon transfection, K8, K18, and K19 are modified by poly-SUMO-2/3 chains on Lys-285/Lys-364 (K8), Lys-207/Lys-372 (K18), and Lys-208 (K19). Sumoylation affects filament organization and stimulus-induced keratin solubility and is partially inhibited upon mutation of one of three known K8 phosphorylation sites. Extensive sumoylation occurs in cells transfected with individual K8, K18, or K19 but is limited upon heterodimerization (K8/K18 or K8/K19) in the absence of stress. In contrast, keratin sumoylation is significantly augmented in cells and tissues during apoptosis, oxidative stress, and phosphatase inhibition. Poly-SUMO-2/3 conjugates are present in chronically injured but not normal, human, and mouse livers along with polyubiquitinated and large insoluble keratin-containing complexes. Notably, common human K8 liver disease-associated variants trigger keratin hypersumoylation with consequent diminished solubility. In contrast, modest sumoylation of wild type K8 promotes solubility. Hence, conformational changes induced by keratin natural mutations and extensive tissue injury result in K8/ K18/K19 hypersumoylation, which retains keratins in an insoluble compartment, thereby limiting their cytoprotective function.

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“…For in vivo oxidative liver damage, mice were fed with a hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 3 weeks to induce chronic oxidative stress in the liver (29).…”

Section: Methodsmentioning

confidence: 99%

Wnt/β-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3

Guo

Lehwald

Jang

et al. 2013

Journal of Biological Chemistry

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114

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Background: Wnt/␤-catenin signaling regulates various hepatocellular processes; however, it remains unexplored whether ␤-catenin provides hepatocyte protection against oxidative stress-induced apoptosis. Results: Mice with ␤-catenin-deficient hepatocytes demonstrate significantly increased hepatotoxin-induced liver injury. Conclusion: Hepatic ␤-catenin signaling confers hepatocyte protection against oxidative stress-induced apoptosis. Significance: Our findings have relevance for potential future therapies directed at hepatocyte protection, regeneration, and anti-cancer treatment.

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Gender Dimorphic Formation of Mouse Mallory–Denk Bodies and the Role of Xenobiotic Metabolism and Oxidative Stress

Cited by 47 publications

References 45 publications

Lamin aggregation is an early sensor of porphyria-induced liver injury

Lamin aggregation is an early sensor of porphyria-induced liver injury

Keratin Hypersumoylation Alters Filament Dynamics and Is a Marker for Human Liver Disease and Keratin Mutation

Wnt/β-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3

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