Hepatitis C virus–induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity

Miura, Kouichi; Taura, Kojiro; Kodama, Yuzo; Schnabl, Bernd; Brenner, David A.

doi:10.1002/hep.22486

Cited by 254 publications

(219 citation statements)

References 39 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…Our findings, including the reduced hepcidin/ferritin ratio and correlation between hepcidin and ferritin concentrations fit well with reports showing that hepcidin induction was relatively impaired in CHC patients, but also that its regulation by iron stores was maintained (13,14). These findings are also in agreement with recent studies in animal and cellular models suggesting that HCV suppresses hepcidin production and may contribute to the development of iron overload in CHC (19,20).…”

Section: Discussionsupporting

confidence: 92%

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

et al. 2010

View full text Add to dashboard Cite

Aim In chronic hepatitis C, iron might play an important role as a hepatotoxic co-factor. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy. To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFEhemochromatosis. Methods Fourteen Japanese patients with chronic hepatitis C and eight Italian patients with HFEhemochromatosis underwent repeated venesection with a serum ferritin endpoint of 20 and 50 ng/mL, respectively. Serum iron indices and liver function tests were measured in pre-and post treatment blood samples from each patient. Body iron stores were calculated using the removed blood volume. Results In both patients with hepatitis and hemochromatosis, serum ferritin, aminotransferase and hepcidin 25 were reduced after venesection. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients (11.1 ± 9.2 ng/mL), but not so in hepatitis patients (30.7 ± 14.5 ng/mL). Inversely, the estimated body iron stores of hemochromatosis patients were 5,960 ± 2,750 mg, while those of hepatitis patients were 730 ± 560 mg. Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients. Conclusion Even though the threshold of iron hepatotoxicity and benefit of its removal differ between patients with chronic hepatitis C and those with HFE-hemochromatosis, venesection is a valid choice of treatment to reduce liver disease activity in both diseases.

show abstract

Section: Discussionsupporting

confidence: 92%

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

et al. 2010

View full text Add to dashboard Cite

show abstract

“…However, in most cases, hepcidin was found suppressed during chronic HCV infection, 12,13 possibly because of ROS-mediated reduction in HAMP gene expression. 14 On the other hand, HCV-driven inflammation may counteract ROS-induced hepcidin repression, since elevated IL-6 stimulates HAMP gene transcription. 15 This second level of dichotomy merely stresses our incomplete understanding of the nature of the interactions between HCV and iron homeostasis at various disease stages.…”

Section: Introductionmentioning

confidence: 99%

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

View full text Add to dashboard Cite

Mechanisms that favor Hepatitis C virus (HCV) persistence over clearance are unclear, but involve defective innate immunity. Chronic infection is characterized by hepatic iron overload, hyperferraemia and hyperferittinaemia. Hepcidin modulates iron egress via ferroportin and its storage in ferritin. Chronic HCV patients have decreased hepcidin, while HCV replication is modified by HAMP silencing. We aimed to investigate interactions between HCV and hepcidin, during acute and chronic disease, and putative alterations in cellular iron homeostasis that enhance HCV propagation and promote viral persistence. Thus, we used HCV JFH-1-infected co-cultures of Huh7.5 hepatoma and THP-1 macrophage cells, HCV patients' sera and Huh7 hepcidin-expressing cells transfected with HCV replicons. Hepcidin levels were elevated in acutely infected patients, but correlated with viral load in chronic patients. HAMP expression was up-regulated early in HCV infection in vitro, with corresponding changes in ferritin and FPN. Hepcidin overexpression enhanced both viral translation and replication. In HCV-infected co-cultures, we observed increased hepcidin, reduced hepatoma ferritin and a concurrent rise in macrophaghic ferritin over time. Altered iron levels complemented amplified replication in hepatoma cells and one replication round in macrophages. Iron-loading of macrophages led to enhancement of hepatic HCV replication through reversed ferritin "flow." Viral transmissibility from infected macrophages to na€ ıve hepatoma cells was induced by iron. We propose that HCV control over iron occurs both by intracellular iron sequestration, through hepcidin, and intercellular iron mobilisation via ferritin, as means toward enhanced replication. Persistence could be achieved through HCV-induced changes in macrophagic iron that enhances viral replication in these cells.

show abstract

“…HDAC6 has also been implicated in the establishment of chronic infection of HCV. Miura et al have demonstrated that chronic HCV infection induces the accumulation of reactive oxygen species and subsequently evokes HDAC activity, which, in turn, deacetylates histones and regulates the location and activities of hypoxiainducible factors, CCAAT/enhancer binding protein a and signal transducers and activators of transcription 3 to suppress the expression of hepcidin, a key negative regulator of iron availability [137]. Sustained low hepcidin expression may contribute to the elevated iron accumulation in the liver and chronic hepatitis.…”

Section: Facilitating Viral Pathogenesismentioning

confidence: 99%

Cellular defence or viral assist: the dilemma of HDAC6

Zheng

Jiang

et al. 2017

Journal of General Virology

View full text Add to dashboard Cite

Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and b-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylaseand ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch.

show abstract

Hepatitis C virus–induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity

Cited by 254 publications

References 39 publications

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

Cellular defence or viral assist: the dilemma of HDAC6

Contact Info

Product

Resources

About