Cytoskeletal alterations leading to Mallory body formation in livers of mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine

Tsunoo, Chisa; Harwood, Thomas R.; Arak, Saima; Yokoo, Hidejiro

doi:10.1016/s0168-8278(87)80065-x

Cited by 20 publications

(14 citation statements)

References 13 publications

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“…9 -15 MBs can be reproduced in mice by chronic intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). 16 Using mass spectrometry, we identified p62 as a novel and major component of MBs isolated from DDC intoxicated mouse livers. p62 (also designated STAP, A170, and ZIP) was originally identified as a ligand for the SH2 domain of p56 lck17-20 and was shown to contain several functional domains, such as a zinc finger motif, proline rich regions, and a PEST sequence.…”

mentioning

confidence: 99%

p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases

Zatloukal¹,

Stumptner²,

Fuchsbichler³

et al. 2002

The American Journal of Pathology

567

444

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confidence: 99%

p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases

Zatloukal¹,

Stumptner²,

Fuchsbichler³

et al. 2002

The American Journal of Pathology

567

444

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“…For example, human and mouse hepatocytes may develop and accumulate Mallory‐Denk bodies, which consist of intracellular protein aggregates comprising mostly keratins, as a result of several molecular alterations, including transamidation of keratins (18, 19). In mice, long‐term ingestion of porphyrinogenic toxins such as 5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) also leads to Mallory‐Denk body formation (20). In addition to the phototoxicity of porphyrins, oxidative stress also occurs in the absence of light.…”

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confidence: 99%

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

et al. 2016

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Protoporphyria is a metabolic disease that causes excess production of protoporphyrin IX (PP-IX), the final biosynthetic precursor to heme. Hepatic PP-IX accumulation may lead to end-stage liver disease. We tested the hypothesis that systemic administration of porphyrin precursors to zebrafish larvae results in protoporphyrin accumulation and a reproducible nongenetic porphyria model. Retro-orbital infusion of PP-IX or the iron chelator deferoxamine mesylate (DFO), with the first committed heme precursor α-aminolevulinic acid (ALA), generates high levels of PP-IX in zebrafish larvae. Exogenously infused or endogenously produced PP-IX accumulates preferentially in the liver of zebrafish larvae and peaks 1 to 3 d after infusion. Similar to patients with protoporphyria, PP-IX is excreted through the biliary system. Porphyrin accumulation in zebrafish liver causes multiorganelle protein aggregation as determined by mass spectrometry and immunoblotting. Endoplasmic reticulum stress and induction of autophagy were noted in zebrafish larvae and corroborated in 2 mouse models of protoporphyria. Furthermore, electron microscopy of zebrafish livers from larvae administered ALA + DFO showed hepatocyte autophagosomes, nuclear membrane ruffling, and porphyrin-containing vacuoles with endoplasmic reticulum distortion. In conclusion, systemic administration of the heme precursors PP-IX or ALA + DFO into zebrafish larvae provides a new model of acute protoporphyria with consequent hepatocyte protein aggregation and proteotoxic multiorganelle alterations and stress.-Elenbaas, J. S., Maitra, D., Liu, Y., Lentz, S. I., Nelson, B., Hoenerhoff, M. J., Shavit, J. A., Omary, M. B. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.

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“…Experimental long-term intoxication of mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or griseofulvin (GF) mimics the particular hepatocellular alterations associated with AH, ie, ballooning of hepatocytes, accumulation of MBs, and alterations of the cytokeratin IF network. [27][28][29][30][31] These animal models are valuable not only for investigating the effects of long-term (chronic) intoxication (ie, for 2 to 4 months) but also for assessing the time course of alterations finally leading to MB formation and cytokeratin filament derangement. In addition to elucidating mechanisms involved in the pathogenesis of AH, these DDC and GF animal models may provide insight into biology and pathology of cytokeratins.…”

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confidence: 99%

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Stumptner¹,

Omary²,

Fickert³

et al. 2000

The American Journal of Pathology

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Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies , termed Mallory bodies (MBs).Cytokeratins are members of the large family of intermediate filament (IF) cytoskeletal proteins, which are normally expressed in a tissue-specific manner and assembled as cytoplasmic filamentous arrays. Neurofilaments, ␣-internexin, desmin, vimentin, glial filaments, and the nuclear lamins 1,2 also belong to the IF family. The diverse cell biological functions of IFs are still poorly understood. However, a diversity of human diseases is associated with severe alterations of IFs. A common pathological feature of many IF-related diseases is the accumulation of intracytoplasmic inclusions consisting of modified IF proteins, for example in neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Lewy body dementia 3-6 ; in neuromuscular disorders (eg, spheroid body myositis 7 ); and the formation of Mallory bodies (MBs) in alcoholic hepatitis (AH) and other liver disorders (eg, non-alcoholic steatohepatitis, Wilson's disease, primary biliary cirrhosis, Indian childhood cirrhosis, hepatocellular neoplasms 8 -11 ). Although the underlying pathogenetic mechanisms are as yet unclear, posttranslational modifications of IF proteins, such as phosphorylation, limited proteolysis, and crosslinking, may play a major role. For example, the presence of hyperphosphorylated neurofilament epitopes in some neuronal inclusion bodies 12-15 and of abnormally phosphorylated desmin in muscle fibers 16 were reported. Furthermore, a possible association of cytokeratin hyperphosphorylation with the formation of MBs in hepatocytes, a hallmark of AH, was suggested by in vitro and animal studies performed by our own group and others. [17][18][19][20] AH follows chronic alcohol abuse and occurs in 20 to 40% of heavy drinkers. Although reversible at the beginning, most cases of AH progress to irreversible cirrhosis. Besides the amount of alcohol ingested per day, a variety of other factors such as dietary habits, genetic factors influencing alcohol metabolism, viral infections, and additional toxins or drugs seem to determine the extent of liver damage. Classical morphological features of AH are liver cell ballooning and necrosis, inflammation, steatosis, and the formation of cytokeratin-containing MBs, which is associated with severe derangement (ie, diminution or even loss) of the hepatocyte cytokeratin IF network. 8 -11,22-26 Diverse animal models have been generated to study in more detail and under defined conditions mechanisms involved in the pathogenesis of this alcoholic liver disease. Experimental long-term intoxication of mice with Supported by the grants of the Austrian Science Foundation S7401-MOB (to K. Z.) and 7628-MED (to H. D.) and by a U.S. Veterans Affairs Merit and Career Development Award (to M. B. O.).

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Cytoskeletal alterations leading to Mallory body formation in livers of mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine

Cited by 20 publications

References 13 publications

p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases

p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

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