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<p>Type I interferons are secreted in response to various stimuli and are used as a treatment for many diseases, including infections with the hepatitis B virus (HBV) and its satellite virus, hepatitis delta (HDV). HDV significantly aggravates HBV-mediated liver damage and is – in contrast to HBV - a strong inducer of interferon responses, including IFN-β. As the role of IFN- β in liver metabolism is so far ill explored, we studied its impact on hepatocyte metabolism in HDV-infected cultures. Transcriptome analysis, isotope tracing and functional tests on differentiated, HDV-infected hepatocytes showed reduction of mitochondrial TCA cycle and respiratory activity and increases in serine, asparagine and glutathione synthesis. Furthermore, the stress-response factor ATF4 was activated by IFN-β via yet unidentified non-canonical mechanisms and mediated resistance to oxidants. IFN-β furthermore reduced the expression and activity of liver differentiation markers. Thus, IFN-β-mediated dedifferentiation and stress-resistance may contribute to HDV-associated liver pathology.</p>

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IFN-β production promotes metabolic rewiring and protection against oxidative stress in hepatitis delta virus-infected hepatocyte cultures

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月18日

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  • Olga A. Khomich,
  • Patrick Giavalisco,
  • Romain Parent,
  • George S. Krasnov,
  • Peter Tessarz,
  • Philip Meuleman,
  • Rani Burm,
  • Natalia F. Zakirova,
  • Jennifer Molle,
  • Enkhtuul Batbold,
  • Eyal Gottlieb,
  • Fabien Zoulim,
  • Alexander V. Ivanov,
  • Birke Bartosch

摘要

Type I interferons are secreted in response to various stimuli and are used as a treatment for many diseases, including infections with the hepatitis B virus (HBV) and its satellite virus, hepatitis delta (HDV). HDV significantly aggravates HBV-mediated liver damage and is – in contrast to HBV - a strong inducer of interferon responses, including IFN-β. As the role of IFN- β in liver metabolism is so far ill explored, we studied its impact on hepatocyte metabolism in HDV-infected cultures. Transcriptome analysis, isotope tracing and functional tests on differentiated, HDV-infected hepatocytes showed reduction of mitochondrial TCA cycle and respiratory activity and increases in serine, asparagine and glutathione synthesis. Furthermore, the stress-response factor ATF4 was activated by IFN-β via yet unidentified non-canonical mechanisms and mediated resistance to oxidants. IFN-β furthermore reduced the expression and activity of liver differentiation markers. Thus, IFN-β-mediated dedifferentiation and stress-resistance may contribute to HDV-associated liver pathology.