Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies

Ku, Nam Su; Darling, Jama M.; Krams, Sheri M.; Esquivel, Carlos O.; Keeffe, Emmet B.; Sibley, Richard K.; Lee, Y. M.; Wright, Teresa L.; Omary, M. Bishr

doi:10.1073/pnas.0936165100

Cited by 97 publications

(91 citation statements)

References 32 publications

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“…However, the fourth phosphorylation site (K18 S33) increased in noncirrhotic liver disease (possibly due to cell regeneration) then decreased in cirrhosis (possibly due to the observed apoptosis). In the case of cirrhosis, increased keratin phosphorylation (Fig.1) was independent of the presence or absence of the most common liver disease patient-associated K8 mutation (G61C) described to date 10 This suggests that keratin hyperphosphorylation can be used as a marker also in patients with keratin mutations. The association of keratin phosphorylation with liver disease severity shows the best concordance if multiple sites are concurrently analyzed.…”

Section: Discussionmentioning

confidence: 82%

Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Toivola

Resurreccion

et al. 2004

Hepatology

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Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. (HEPATOLOGY 2004;40:459 -466.)

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Section: Discussionmentioning

confidence: 82%

Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Toivola

Resurreccion

et al. 2004

Hepatology

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“…It has been suggested that hepatocellular proliferative lesions that are positive for GST-P in rats can be demonstrated by the overexpression of CK8 and CK18 complex through CK8 phosphorylation [16]. Ku reported that mutations of CK8 and CK18 are risk factors for developing human liver diseases [20]. CK8/18 mutations may trigger oxidative injury in hepatocytes [32], and such an overexpression of CK8/18 is maintained in human hepatocellular carcinomas [2].…”

Section: Discussionmentioning

confidence: 99%

Cytokeratin 8/18 is a Useful Immunohistochemical Marker for Hepatocellular Proliferative Lesions in Mice

Kawai

Saegusa

Kemmochi

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. In order to clarify whether cytokeratin (CK) 8/18 is a useful immunohistochemical marker for hepatocellular proliferative lesions in mice, partially hepatectomized male ICR mice were given 0.6% piperonyl butoxide (PBO) for 8 (Experiment I) or 25 weeks (Experiment II) after N-diethylnitrosamine (DEN) initiation treatment, and the livers were subjected to histological examinations on hematoxylin and eosin (HE) stained sections, CK8/18 immunohistochemistry and gamma-glutamyl transpeptidase (GGT) histochemistry. In Experiment I, the multiplicity of hepatocellular foci in paraffin-embedded sections which were observed in HE-stained sections and positive for CK8/18 was 10.17 and 18.50, respectively, while that of hepatocellular foci in frozen sections which were observed in HEstained sections and positive/negative for GGT was 6.17 and 8.17, respectively. In Experiment II, the total multiplicity of hepatocellular foci in paraffin-embedded sections which were observed in HE-stained sections and positive/negative for CK8/18 was 4.47 and 23.17, respectively, while that of hepatocellular foci in frozen sections which were observed in HE-stained sections and positive/negative for GGT was 2.50 and 3.50, respectively. Most of the hepatocellular adenomas and carcinomas observed in HE-stained sections were positive for CK8/18, but some of the adenomas were negative for CK8/18. These findings indicate that more hepatocellular proliferative lesions can be detected in CK8/18 immunohistochemistry in addition to those observed in HE-stained sections, and suggest that CK8/ 18 may become a useful immunohistochemical marker for detecting hepatocellular proliferative lesions in mice. The rat liver medium-term bioassay system first established by Ito et al. [14] has been repeatedly used for the detection of carcinogenic or tumor promoting potential of chemical substances and has a great advantage due to reproducibility and reliability for generation of data within 8 weeks [8]. For assessment of promoting effects of the test chemicals, glutathione S-transferase placental form (GST-P)-positive foci are used as the primary endpoint. Moreover, since production of GST-P positive foci has been closely correlated with the actual tumor yields [11,21], they are regarded as the reliable preneoplastic lesion in rats. However, it is generally recognized that this immunohistochemical marker is not reactive for liver preneoplastic and neoplastic lesions of mice. It has been shown that gammaglutamyl transpeptidase (GGT) play a role in multistage hepatocarcinogenesis and the enhanced expression of this enzyme is observed in preneoplastic altered hepatocellular foci, hepatocellular adenomas, and hepatocellular carcinomas in rats and mice [13]. Therefore, GGT is used as a histochemical marker for these proliferative lesions in mice. However, this histochemical staining of GGT is not suitable for routine histopathological examinations, because frozen sections are necessary for this staining. In addition, there is a disadvantage that almost all th...

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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

226

236

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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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Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies

Cited by 97 publications

References 32 publications

Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Cytokeratin 8/18 is a Useful Immunohistochemical Marker for Hepatocellular Proliferative Lesions in Mice

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

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