Mutation of human keratin 18 in association with cryptogenic cirrhosis.

Ku, Nam Su; Wright, Teresa L.; Terrault, Norah A.; Gish, Robert G.; Omary, M. Bishr

doi:10.1172/jci119127

Cited by 109 publications

(73 citation statements)

References 33 publications

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“…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. 42 Both CD95 as well as CD95L have been shown to be up-regulated in chronic HCV infection.…”

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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“…57 Structure and function of the cytokeratin IF cytoskeleton is not only affected by gene mutations but is also rapidly and reversibly modulated by posttranslational modifications, thus making the cytokeratin IF cytoskeleton a potential target for a variety of environmental factors. 41 Phosphorylation is one of the most important means of regulating protein function in response to extracellular stimuli.…”

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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“…9,11,45 The most common causes, such as viral and autoimmune hepatitis, or alcoholic use of K8/18 as tumor markers involves staining of tissue liver disease. 39 The low frequency of the identified K18 mutafrom tumor specimens to clarify their cell origin. 42,43 Measuretion makes it unlikely to be a polymorphism, but, more imporment of the serum component ''tissue polypeptide antigen,'' tantly, the mutation was associated with a filament-assembly which consists of K8/18/19, 46 in cancer patients' serum has defect if introduced into a recombinant K18 protein and anabeen tested as a hepatoma tumor marker but did not compare lyzed in vitro.…”

Section: Disease Association With If Proteinsmentioning

confidence: 99%

“…42,43 Measuretion makes it unlikely to be a polymorphism, but, more imporment of the serum component ''tissue polypeptide antigen,'' tantly, the mutation was associated with a filament-assembly which consists of K8/18/19, 46 in cancer patients' serum has defect if introduced into a recombinant K18 protein and anabeen tested as a hepatoma tumor marker but did not compare lyzed in vitro. 39 Although familial idiopathic cases of liver in specificity to a-fetoprotein. 47 With regard to the patients disease are unusual, 40 the involvement of K8/18 mutations with autoimmune hepatitis who develop antibodies to soluble in liver disease is attractive on several fronts.…”

Section: Disease Association With If Proteinsmentioning

confidence: 99%

See 1 more Smart Citation

Intermediate filament proteins of the liver: Emerging disease association and functions

Omary¹,

Ku²

1997

Hepatology

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1. Summary of mouse data that involve keratin overexpression, gene disruption, and ectopic expession. The overexpression constructs utilized genomic clones that maintain tissue-specific expression of the indicated keratins. Mice with ''normal'' phenotype are defined as those with normal organ histology, and, in the case of the mice that overexpress WT K18, they are also ''normal'' in that they tolerated liver perfusion for hepatocyte isolation and responded to acetaminophen and griseofulvin in a manner that was similar to their nontransgenic counterparts. 18,22,23 Such ''normal'' phenotype depends on the transgene copy number and amount of protein expressed, because expression of supraphysiological and extremely high levels of WT K8 or K8/K18 in transgenic mice can be detrimental (Jorcano J, Baribault H, et al., respectively, unpublished observations, January 1997). The K18-null mice manifest liver histological features that are similar to that found in mice that overexpress arg89 r cys K18 (Magin T, personal communication, January 1997). K19 gene disruption was performed by interrupting the gene with a lac Z cassette, and no histological defects were noted in the hepatobiliary system (Tamai Y, Taketo M, personal communication, December 1996

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Mutation of human keratin 18 in association with cryptogenic cirrhosis.

Cited by 109 publications

References 33 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

Intermediate filament proteins of the liver: Emerging disease association and functions

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