S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling<i>in vitro</i>

Duong, François H. T.; Christen, Verena; Sinnreich, Magdalena Filipowicz; Heim, Markus H.

doi:10.1002/hep.21116

Cited by 80 publications

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“…8,12,13 This study now provides a unifying hypothesis how these completely unrelated viruses induce a similar cellular response that finally leads to an inhibition of IFN␣ signaling. Both viruses activate an ER stress response, and through the Ca 2ϩ -dependent activation of CREB transcriptionally up-regulate PP2Ac, a key enzyme for many cellular processes.…”

Section: Discussionmentioning

confidence: 75%

“…8,11 PP2A overexpression is the key event in this cascade, and indeed, PP2A was consistently found to be overexpressed in cell lines expressing HCV proteins, in liver extracts of HCV transgenic mice, and in liver biopsies of patients with CHC. 11,12 Recently, we found an induction of PP2A in liver biopsies from patients with chronic hepatitis B (CHB), and in cell lines that express HBV proteins. 13 The finding was surprising because HBV and HCV are not related.…”

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confidence: 99%

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Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A

et al. 2007

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The up-regulation of protein phosphatase 2 A (PP2A) is an important factor leading to an inhibition of IFN␣ signaling caused by viral protein expression. Here, we describe the molecular mechanism involved in PP2Ac up-regulation by HCV and HBV. HCV and HBV protein expression in cells induces an ER stress response leading to calcium release from the ER. HCV protein expression induces CREB activation, probably through calcium/calmodulin-dependent protein kinase. CREB binds to a CRE element in the promoter of PP2Ac and induces its transcriptional up-regulation. Because PP2Ac is involved in many important cellular processes including cell-cycle regulation, apoptosis, cell morphology, development, signal transduction and translation, its up-regulation during ER stress has potentially important implications. (HEPATOLOGY 2007;46:558-565.)

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Section: Discussionmentioning

confidence: 75%

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Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A

et al. 2007

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“…Hepatocytes accumulate lipid when its synthesis, uptake, secretion and/or utilization are altered (Browning and Horton, 2004;Fromenty et al, 2004). Although the events that initiate most steatotic disorders are now beginning to be more clearly defined, it has been recognized for many years that methionine metabolism, which is altered in patients with alcoholic liver disease and other chronic liver disorders associated with steatosis, may play a contributory role (Diehl, 2005;Duong et al, 2006;Esfandiari et al, 2005;Innis and Hasman, 2006;Kharbanda, 2007;Lu et al, 2002;Mato et al, 2008;Wortham et al, 2008;Zhu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

et al. 2009

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Hepatic steatosis and liver degeneration are prominent features of the zebrafish ducttrip (dtp) mutant phenotype. Positional cloning identified a causative mutation in the gene encoding S-adenosylhomocysteine hydrolase (Ahcy). Reduced Ahcy activity in dtp mutants led to elevated levels of S-adenosylhomocysteine (SAH) and, to a lesser degree, of its metabolic precursor Sadenosylmethionine (SAM). Elevated SAH in dtp larvae was associated with mitochondrial defects and increased expression of tnfa and pparg, an ortholog of the mammalian lipogenic gene. Antisense knockdown of tnfa rescued hepatic steatosis and liver degeneration in dtp larvae, whereas the overexpression of tnfa and the hepatic phenotype were unchanged in dtp larvae reared under germ-free conditions. These data identify an essential role for tnfa in the mutant phenotype and suggest a direct link between SAH-induced methylation defects and TNF expression in human liver disorders associated with elevated TNFα. Although heterozygous dtp larvae had no discernible phenotype, hepatic steatosis was present in heterozygous adult dtp fish and in wildtype adult fish treated with an Ahcy inhibitor. These data argue that AHCY polymorphisms and AHCY inhibitors, which have shown promise in treating autoimmunity and other disorders, may be a risk factor for steatosis, particularly in patients with diabetes, obesity and liver disorders such as hepatitis C infection. Supporting this idea, hepatic injury and steatosis have been noted in patients with recently discovered AHCY mutations.

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“…Interestingly, in vitro S-adenosyl methionine (SAMe; the principal methyl donor for STAT1) combined with betaine was found to reverse HCV blockade of IFN-α/β signaling. 24 These findings have led to pilot studies testing whether the addition of SAMe and betaine to peginterferon will improve responses in patients with chronic hepatitis C who are nonresponders to optimal therapy. HCV may also be able to modulate antiviral responses in the host through interactions with elements of the inflammatory response.…”

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Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

et al. 2007

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The current recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin, which results in a sustained clearance of hepatitis C virus (HCV) in at least half of patients. However, the mechanisms by which interferon alpha (IFN-α) and ribavirin act against HCV are not well defined. The importance of understanding the biological pathways, cellular effects, and antiviral activities of these agents is underscored by clinical observations that nonresponders frequently have little or no decrease in HCV RNA levels during treatment, suggesting intrinsic resistance to IFN-α. Cell culture and animal models of HCV have shown that the infection itself may block IFN-α induction and action. Still other findings suggest that individual innate and adaptive immune responses, host genetic factors, viral genetic diversity, and clinical comorbidities account for part of nonresponse to therapy. To provide an overview of the current knowledge of the mechanisms of action of IFN-α and ribavirin against HCV and offer guidance for future research, the American Association for the Study of Liver Diseases held a single topic conference entitled "Interferon and Ribavirin in Hepatitis C Virus Infection: Mechanisms of Response and Non-Response" on March [1][2][3] 2007. This article summarizes that conference. Interferons (IFNs): An OverviewThe IFNs (Dr. Howard Young, National Cancer Institute, National Institutes of Health)The type 1 IFNs [interferon alpha and beta (IFN-α/β)] comprise a family of distinct proteins1 that are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes, 2 although plasmacytoid dendritic cells (DCs) are probably the major source in most viral infections. In contrast, type II IFN [interferon gamma (IFN-γ)] is a single gene cytokine unrelated in structure to IFN-α/β that is produced largely by macrophages, natural Copyright © 2007 by the American Association for the Study of Liver Diseases.Address reprint requests to: Raymond T. Chung, M.D., Gastrointestinal Unit, GRJ724, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. rtchung@partners.org; fax: 617-643-0446.. Potential conflict of interest: Dr. Lemon is a consultant for Novartis, GlaxoSmithKline, Hoffman-LaRoche, Genelabs Technology, Abbott, Pharmasett. He also received grants from Schering-Plough and Tibotec. Dr. Chung received grants from Roche and ScheringPlough. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2009 December 29. Published in final edited form as:Hepatology. 2008 January ; 47(1): 306-320. doi:10.1002/hep.22070. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript killer (NK) cells, and T lymphocytes. Both types of IFNs interact with cells via distinct cellular receptors. The details of the signaling mechanisms by which IFN-α/β and IFN-γ induce the transcription of interferon-stimulated genes (ISGs) and depress the transcription of others are still being defined. 3 However, it is increasingly clear that the c...

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S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signalingin vitro

Abstract: Hepatitis C virus (HCV) infection is

Cited by 80 publications

References 52 publications

Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A

Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A

TNFα-dependent hepatic steatosis and liver degeneration caused by mutation of zebrafishs-adenosylhomocysteine hydrolase

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

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