Telomere Shortening in Chronic Liver Diseases

Kitada, Takuya; Seki, Shuichi; Kawakita, Nobuyoshi; Kuroki, Tetsuo; Monna, Takeyuki

doi:10.1006/bbrc.1995.1774

Cited by 135 publications

(84 citation statements)

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“…[39][40][41] These findings indicate that hTERT activity in human hepatocytes is not sufficient to completely maintain telomeres at a stable length in chronically damaged liver. These data stand in line with the observation that human hematopoietic stem cells express low levels of telomerase but yet experience age-dependent telomere shortening.…”

Section: Discussionmentioning

confidence: 95%

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

et al. 2011

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Section: Discussionmentioning

confidence: 95%

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

et al. 2011

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“…[9][10][11][12][25][26][27][28] Because it is well known that telomere length is genetically defined before replicative history, and distributes widely among individuals, 8 comparison of TRF length without any standardization among individuals may be one of the reasons for these controversial results. In this study, we compared RTC value after normalization of TC in the liver by referencing that in autologus PBL.…”

Section: Discussionmentioning

confidence: 99%

“…8 Although this variation should be normalized before comparison of telomere length among patients, all previous reports describing telomere alteration in chronic liver diseases were unfortunately evaluated without any standardization. [9][10][11][12] These technical limitations inherent in the complexity of TRF make it difficult to analyze telomere dynamics using clinical materials, especially in the case that only a small specimen is available.…”

mentioning

confidence: 99%

Reduction of telomeric repeats as a possible predictor for development of hepatocellular carcinoma: Convenient evaluation by slot-blot analysis

et al. 1999

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Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, and hepatitis B and C viruses are the main causative agents for high incidence of HCC. 1 Although the mechanisms underlying HCC development have been widely investigated from both points of direct and indirect effects of the viruses, 2 they are still open to debate. Whatever the mechanisms involved, these viral infections are correlated with a slow, long-lasting disease that is a definite risk for neoplastic degeneration.Telomeres are composed of tandem arrays of a short DNA sequence, d(TTAGGG)n in vertebrates, and associated proteins. They are essential genetic elements and stabilize the natural ends of linear eukaryotic chromosomes. 3 The endreplication problem, the inability of DNA polymerases to completely replicate the end of a DNA duplex, 4 results in telomere shortening in proportion to cell replication. 5 Because severity of persistent hepatocellular degeneration might indicate a risk for HCC development, an extent of telomere erosion has a possibility to be a predictor for HCC development in the liver under chronic inflammation.The standard and currently most reliable method for evaluating telomere length uses Southern analysis of terminal restriction fragment (TRF) lengths. 6 TRFs, however, contain DNA other than uniform telomeric repeats, 7 and the analysis requires several micrograms of high-molecular-weight genomic DNAs. In addition, telomere length varies among individuals prior to replicative histories. 8 Although this variation should be normalized before comparison of telomere length among patients, all previous reports describing telomere alteration in chronic liver diseases were unfortunately evaluated without any standardization. 9-12 These technical limitations inherent in the complexity of TRF make it difficult to analyze telomere dynamics using clinical materials, especially in the case that only a small specimen is available.In this study, we first evaluated reliability and reproducibility of a slot-blot analysis to detect alteration of telomeric repeats content. Next, we determined the content in various liver tissues. For comparison of the content in the liver with respect to chronic inflammation, we standardized the content

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“…Given that telomere shortening and/or impaired telomerase activity have been linked to the development of progressive fibrosis in chronic liver injury [9][10][11][12], it is likely that enhanced telomerase activity serves a protective function. One means by which telomerase may confer protection during chronic liver injury is through the prevention of telomere shortening with its resultant replicative arrest and senescence.…”

Section: Discussionmentioning

confidence: 99%

“…This concept is supported by studies demonstrating that the telomeres of chronically diseased human livers are shorter than those of age-matched controls [9][10][11] Although relatively little work has been done examining the effects of liver injury on telomeres in experimental animals, the available data are intriguing. For example, mice with a targeted deletion of one of the components of telomerase demonstrate impaired hepatic regeneration and accelerated fibrogenesis in the context of liver injury [12].…”

Section: Introductionmentioning

confidence: 98%

Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state?

Brown

Mathahs²,

Broadhurst³

et al. 2007

Free Radical Biology and Medicine

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Telomeres are repeated sequences at chromosome ends that are incompletely replicated during mitosis. Telomere shortening caused by proliferation or oxidative damage culminates in replicative arrest and senescence, which may impair regeneration during chronic liver injury. While the effects of experimental liver injury on telomeres have received little attention, prior studies suggest that telomerase, the enzyme complex that catalyzes the addition of telomeric repeats, is protective in some rodent liver injury models. Thus, the aim of this study was to determine the effects of iron overload on telomere length and telomerase activity in rat liver. Mean telomere lengths were similar in ironloaded and control livers. However, telomerase activity was increased 3-fold by iron loading with no change in levels of TERT mRNA or protein. Because thiol redox state has been shown to modulate telomerase activity in vitro, hepatic thiols were assessed. Significant increases in GSH (1.5-fold), cysteine (15-fold), and glutamate cysteine ligase activity (1.5-fold) were observed in iron-loaded livers, while telomerase activity was inhibited by treatment with N-ethylmaleimide. This is the first demonstration of increased telomerase activity associated with thiol alterations in vivo. Enhanced telomerase activity may be an important factor contributing to the resistance of rodent liver to ironinduced damage.

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Telomere Shortening in Chronic Liver Diseases

Cited by 135 publications

References 0 publications

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

Reduction of telomeric repeats as a possible predictor for development of hepatocellular carcinoma: Convenient evaluation by slot-blot analysis

Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state?

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