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Elevated hepatic lipid and interferon stimulated gene expression in HCV GT3 patients relative to non-alcoholic steatohepatitis

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Abstract

Background and aims

HCV GT-3 has a more pronounced effect on hepatic steatosis and host lipids than other HCV genotypes and is proving less responsive to all oral interferon-free treatment with direct acting antiviral agents. As both HCV GT3 infection and NASH can result in steatosis and cirrhosis, we asked whether hepatic transcriptional profiles reflective of the host response to inflammation differed based on the etiology of injury.

Methods

Hepatic gene expression was determined for 48 pre-selected genes known to be associated with hepatic interferon signaling and lipid metabolic pathways in treatment-naïve HCV GT-3 (n = 9) and NASH (n = 14) patients.

Results

Genes with significantly higher expression in HCV included chemokines CXCL10, CXCL11 interferon IFNA2, interferon receptors IFNAR1, IL10RB negative regulators of interferon signaling SOCS3, USP18, JAK/STAT and IRF family members STAT1, STAT2, and IRF, and TGFB family members TGFB1, TGFBR1, and TGFBR2 and other ISGs like OAS2, IF127, IF144 and ISG15. HCV infection was also associated with higher expression of genes associated with lipid metabolism APOE, APOL3, SREBF1 and HMBS. Furthermore, our results suggest that, in HCV GT3-infected patients, IL28B (CC) genotype is associated with lower baseline ISG expression such as IRF9, ISG15, MX1, STAT1, CXCL10, CXCL11, and IFI27 compared to CT/TT genotype.

Conclusions

HCV GT-3 and NASH both induce hepatic steatosis and inflammation, while HCV GT-3 infection is uniquely associated with elevated transcription of hepatic ISGs and genes associated with lipid metabolism. These changes likely reflect the unique host response to HCV replication distinct from the inflammatory response induced by NASH.

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Abbreviations

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AST:

Serum aspartate aminotransferase

CHOL:

Total cholesterol

HCC:

Hepatocellular carcinoma

HCV GT-3:

Hepatitis C virus GT3

IL28 B:

Interleukin 28 B

ISG:

Interferon stimulated genes

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

SVR:

Sustained virological response

TBILI:

Total bilirubin

TRIG:

Triglyceride

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Acknowledgements

We would like to thank all the patients who participated in this study.

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Author notes

    Authors and Affiliations

    1. Institute of Human Virology, University of Maryland, Baltimore, MD, USA

      Shikha Shrivastava, Bhawna Poonia & Shyamasundaran Kottilil

    2. Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

      Eric G. Meissner

    3. National Institute of Allergy and Infectious Diseases, NIH, Bethesda, USA

      Emily Funk & Seerat Poonia

    4. Institute of Liver and Biliary Sciences, New Delhi, India

      Virender Shokeen, Arun Thakur, Shiv Kumar Sarin & Nirupma Trehanpati

    Authors
    1. Shikha Shrivastava
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    2. Eric G. Meissner
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    Corresponding authors

    Correspondence to Nirupma Trehanpati or Shyamasundaran Kottilil.

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    Funding sources

    National Institute of Allergy and Infectious Diseases (NIH), Bethesda, United States and Institute of Liver and biliary Sciences, New Delhi, India, supported this study.

    Conflict of interest

    Shikha Shrivastava, Eric G. Meissner, Emily Funk, Seerat Poonia, Virender Shokeen, Arun Thakur, Bhawna Poonia, Shiv Kumar Sarin, NirupmaTrehanpati and Shyamasundaran Kottilil declare that they have no conflicts of interest to disclose.

    Ethical approval

    The study protocol was approved by institutional ethical committee of Institute of Liver and Biliary Sciences (ILBS), New Delhi, and is in accordance with Declaration of Helsinki 1975.

    Informed consent

    All patients provided written informed consent to participate in the study.

    Additional information

    N. Trehanpati and S. Kottilil contributed equally to this manuscript.

    Appendix

    Appendix

    See Table 2.

    Table 2 TaqMan Micro Fluidic Cards of 48-well formats was custom-designed for the following genes according to the manufacturers’ instructions and assembled into 384-well microfluidic cards (Life Technologies)
    Full size table

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    Shrivastava, S., Meissner, E.G., Funk, E. et al. Elevated hepatic lipid and interferon stimulated gene expression in HCV GT3 patients relative to non-alcoholic steatohepatitis. Hepatol Int 10, 937–946 (2016). https://doi.org/10.1007/s12072-016-9733-6

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    • DOI: https://doi.org/10.1007/s12072-016-9733-6

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