Keratins: Guardians of the liver

Omary, M. Bishr; Ku, Nam Su; Toivola, Diana M.

doi:10.1053/jhep.2002.31165

Cited by 150 publications

(159 citation statements)

References 56 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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“…Previous studies have shown that keratin phosphorylation increases during cellular stress and mitosis as well as in several transgenic mouse models of liver disease. 41,42 Another gene that is upregulated in the group of patients with steatosis alone is a MRS2L encoding a putative magnesium transporter. MRS2L deregulation can promote cell death, because deficiency of external magnesium induces apoptosis in primary cultures of rat hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease

et al. 2005

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real-time quantitative reverse-transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI-TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention. (HEPATOLOGY 2005;42:665-674.)

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“…Thawed tissues were dounced and sonicated in 50 mM mannitol, 2 mM Tris-HCl (pH 7.2). TG activity is based on [1,[4][5][6][7][8][9][10][11][12][13][14] …”

Section: Animal Experiments and Tg2 Activitymentioning

confidence: 99%

Pharmacologic transglutaminase inhibition attenuates drug‐primed liver hypertrophy but not Mallory body formation

Strnad¹,

Siegel²,

Toivola³

et al. 2006

FEBS Letters

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Mallory bodies (MBs) are characteristic of several liver disorders, and consist primarily of keratins with transglutaminase-generated keratin crosslinks. We tested the effect of the transglutaminase-2 (TG2) inhibitor KCC009 on MB formation in a mouse model fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). KCC009 decreased DDC-induced liver enlargement without affecting MB formation or extent of liver injury. TG2 protein and activity increased after DDC feeding and localized within and outside hepatocytes. KCC009 inhibited DDC-induced hepatomegaly by affecting hepatocyte cell size rather than proliferation. Hence, TG2 is a potential mediator of injury-induced hepatomegaly via modulation of hepatocyte hypertrophy, and KCC009-mediated TG2 inhibition does not affect mouse MB formation.

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Keratins: Guardians of the liver

Cited by 150 publications

References 56 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

A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease

Pharmacologic transglutaminase inhibition attenuates drug‐primed liver hypertrophy but not Mallory body formation

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