Protein phosphatase inhibition in normal and keratin 8/18 assembly-incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity

Toivola, Diana M.; Omary, M. Bishr; Ku, Nam Su; Peltola, O.; Baribault, Hélène; Eriksson, John E.

doi:10.1002/hep.510280117

Cited by 66 publications

(65 citation statements)

References 54 publications

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“…[17][18][19][20] CK-18 expression helps to maintain hepatocyte integrity and guards against hepatocyte death and liver diseases. 38,39 It has been recently demonstrated that CK-18 mutations predispose their carriers to develop cryptogenic and noncryptogenic forms of cirrhosis. 40,41 Moreover, CK-18 mutations are associated with increased sensibility toward CD95-induced hepatocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury

Bantel¹,

Lügering²,

Heidemann³

et al. 2004

Hepatology

229

238

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Chronic hepatitis C virus (HCV) infection is characterized by inflammatory liver damageand is associated with a high risk of development of cirrhosis and hepatocellular carcinoma. Although histological examination of liver biopsies is currently the gold standard for the detection of early liver damage, there is a strong need for better noninvasive methods. We recently demonstrated that the proapoptotic activation of caspases is considerably enhanced in histological sections from HCV-infected liver tissue, suggesting an important role of apoptosis in liver damage. Here, we investigated whether caspase activation is detectable also in sera from patients with chronic HCV infection. Using a novel enzyme-linked immunosorbent assay that selectively recognizes a proteolytic neoepitope of the caspase substrate cytokeratin-18, we demonstrate that caspase activity is markedly increased in the sera of HCV patients. Interestingly, while 27% of patients with chronic HCV infection showed normal aminotransferase levels despite inflammatory and fibrotic liver damage, more than 50% of those patients exhibited already elevated serum caspase activity. Moreover, 30% of patients with normal aminotransferase but elevated caspase activity revealed higher stages of fibrosis. In conclusion, compared with conventional surrogate markers such as aminotransferases, detection of caspase activity in serum might be a more sensitive method of detecting early liver injury. Thus, measurement of caspase activity might provide a novel diagnostic tool, especially for patients with normal aminotransferases but otherwise undiagnosed histologically active hepatitis and progressive fibrosis. H epatitis C virus (HCV) is estimated to infect upto 200 million people worldwide-more than 3% of the world population. 1 HCV infection is characterized by inflammatory liver damage and a long viral persistence associated with a high risk of developing cirrhosis and hepatocellular carcinoma. There is increasing evidence suggesting that liver cell damage in chronic HCV infection is mediated by the induction of apoptosis. [2][3][4][5][6] The importance of apoptosis in HCV infection has originally been proposed in view of patho-morphological features, including cell shrinkage and fragmentation of the nucleus-particularly in areas of piecemeal necrosis, the presence of acidophilic bodies, and focal cell dropouts in the liver lobule, which are characteristic features of individually infected hepatocytes. 7 The molecular mechanisms and signal transduction pathways that cause liver cell damage during HCV infection have not been clearly defined. Over the last few years there has been increasing evidence that death receptor/ligand systems, particularly CD95, play a crucial role in liver damage. Both CD95 and its ligand CD95L have been shown to be up-regulated in HCV infection. 8 -11 Various recent studies demonstrate that the key morphological alterations of apoptosis are mediated by a family of intracellular cysteine proteases, called caspases, that cleave several cellul...

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Section: Discussionmentioning

confidence: 99%

Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury

Bantel¹,

Lügering²,

Heidemann³

et al. 2004

Hepatology

229

238

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“…It has recently been shown in mice that CK8 and CK18 become phosphorylated as a consequence of toxic liver injury induced by a variety of substances, such as GF and microcystin. 17,19,58,59 This hyperphosphorylation of cytokeratin appeared to be involved in the cellular response to toxic stress and is not a mere epiphenomenon due to a general deregulation of protein phosphorylation in the course of cell damage. The clearly demonstrated association of increased CK8/18 phosphorylation with a variety of cell stresses 41,60 has been substantiated recently as having a direct or indirect effect on protection from hepatotoxic injury.…”

Section: Discussionmentioning

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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“…10,11 Intestinal cells express different combinations of K7/8/18/19/20 depending on the part of the digestive tract as well as the cell type. 1,2 Hepatocyte keratins are essential in maintaining cellular integrity and protecting from mechanical and other types of stress, 12,13 whereas the stress-related functions of the pancreatic keratins seem to be less prominent. 10,11 Possible other functions of the abundant keratins are insufficiently characterized, but it is known that keratins also participate in interactions with the other cytoskeletal proteins and in the regulation of crucial signaling and other abundant molecules (reviewed by Ku et al 2 ), including 14-3-3 and heat shock proteins.…”

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confidence: 99%

Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18

et al. 2001

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Simple epithelial tissues such as liver and pancreas express keratins 8 (K8) and 18 (K18) as their major intermediate filament proteins. K8 and K18 null mice and transgenic mice that express mutant K18 (K18C) manifest several hepatocyte abnormalities and demonstrate that K8/18 are important in maintaining liver tissue and cell integrity, although other potential functions remain uncharacterized. Here, we report an additional abnormal liver phenotype, which is similar in K8 null, K18 null, and K18C mouse models. Liver histologic examination showed large polynuclear areas that lacked cell membranes, desmosomal structures, and filamentous actin. Similar, but less prominent, areas were observed in the pancreas. The parenchyma outside the polynuclear areas displayed irregular sinusoidal structures and markedly enlarged nuclei. Most K8 null hepatocytes were positive for the proliferating cell nuclear antigen (PCNA) with a doubled DNA content in comparison with the predominantly PCNA-negative wild-type hepatocytes. The distribution of the 14-3-3 protein was also altered in K8 null mice. Taken together, our results indicate that absence of keratin filaments causes disturbances in cellcycle regulation, driving cells into the S-G2 phase and causing aberrant cytokinesis. These effects could stem from disturbed functions of K8/18-dependent cell-cycle regulators, such as the signaling integrator, 14-3-3. (HEPATOLOGY 2001; 34:1174-1183

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Protein phosphatase inhibition in normal and keratin 8/18 assembly-incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity

Cited by 66 publications

References 54 publications

Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury

Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury

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

Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18

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