HCV Core Protein–ISX Axis Promotes Chronic Liver Disease Progression via Metabolic Remodeling and Immune Suppression

Li‐Ting Wang; Shen‐Nien Wang; Shyh‐Shin Chiou; Jhih‐Peng Tsai; Chee‐Yin Chai; Li‐Wen Tseng; Jin‐Ching Lee; Ming‐Hong Lin; Shau‐Ku Huang; Shih‐Hsien Hsu

doi:10.1002/advs.202300644

journal article·2023-08Open access

HCV Core Protein–ISX Axis Promotes Chronic Liver Disease Progression via Metabolic Remodeling and Immune Suppression

Li‐Ting Wang, Shen‐Nien Wang, Shyh‐Shin Chiou, Jhih‐Peng Tsai, Chee‐Yin Chai, Li‐Wen Tseng, Jin‐Ching Lee, Ming‐Hong Lin, Shau‐Ku Huang, Shih‐Hsien Hsu

Advanced Science· Volume 10· Issue 23

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Abstract

Abstract Chronic hepatitis C virus (HCV) infection is an important public health issue. However, knowledge on how the virus remodels the metabolic and immune response toward hepatic pathologic environment is limited. The transcriptomic and multiple evidences reveal that the HCV core protein–intestine‐specific homeobox (ISX) axis promotes a spectrum of metabolic, fibrogenic, and immune modulators (e.g., kynurenine, PD‐L1, and B7‐2), regulating HCV‐infection relevant pathogenic phenotype in vitro and in vivo. In a transgenic mice model, the HCV core protein–ISX axis enhance metabolic disturbance (particularly lipid and glucose metabolism) and immune suppression, and finally, chronic liver fibrosis in a high‐fat diet (HFD)‐induced disease model. Mechanistically, cells with HCV JFH‐1 replicons upregulate ISX and, consequently, the expressions of metabolic, fibrosis progenitor, and immune modulators via core protein‐induced nuclear factor‐κB signaling. Conversely, cells with specific ISX shRNAi inhibit HCV core protein‐induced metabolic disturbance and immune suppression. Clinically, the HCV core level is significantly correlated with ISX, IDOs, PD‐L1, and B7‐2 levels in HCC patients with HCV infection. Therefore, it highlights the significance of HCV core protein–ISX axis as an important mechanism in the development of HCV‐induced chronic liver disease and can be a specific therapeutic target clinically.

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OpenAlex topics: Diabetes and associated disorders · Endoplasmic Reticulum Stress and Disease · Tryptophan and brain disorders

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Affiliations

Department of Life Science National Taiwan Normal University Taipei 116059 Taiwan

Center of Applied Genomics Kaohsiung Medical University Kaohsiung 80708 Taiwan

Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80708 Taiwan

Division of General and Digestive Surgery Department of Surgery Kaohsiung Medical University Hospital Kaohsiung 80708 Taiwan

Department of Surgery College of Medicine Kaohsiung Medical University Hospital Kaohsiung 80708 Taiwan

Division of Pediatric Hematology and Oncology, Department of Pediatrics Kaohsiung Medical University Hospital Kaohsiung 80708 Taiwan

Graduate Institute of Clinical Medicine, College of Medicine Kaohsiung Medical University Kaohsiung 80708 Taiwan

Department of Pathology Kaohsiung Medical University Hospital Kaohsiung 80708 Taiwan

Department of Biotechnology College of Life Science National Sun Yat‐sen University Kaohsiung 804201 Taiwan

Department of Microbiology and Immunology School of Medicine College of Medicine Kaohsiung Medical University Kaohsiung City 80708 Taiwan

Department of Medical Research Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 80708 Taiwan

National Institute of Environmental Health Sciences National Health Research Institutes Miaoli County 35053 Taiwan

Department of Respirology & Allergy Third Affiliated Hospital of Shenzhen University Shenzhen 518020 China

Department of Medicine Division of Allergy and Clinical Immunology Johns Hopkins University School of Medicine Baltimore MD 21287 USA

Funding

Kaohsiung Medical University Chung-Ho Memorial Hospital · Ministry of Science and Technology, Taiwan · Kaohsiung Medical University · National Health Research Institutes

References (45)

Show source-provided references

1. 10.1016/j.jhep.2020.08.00610.1016/j.jhep.2020.08.006 ↗

2. 10.3390/cancers1206135110.3390/cancers12061351 ↗

3. 10.1007/s12026-014-8494-310.1007/s12026-014-8494-3 ↗

4. 10.1016/j.coph.2014.07.01610.1016/j.coph.2014.07.016 ↗

5. 10.1074/jbc.R110.12529410.1074/jbc.R110.125294 ↗

6. 10.1016/j.coph.2016.07.01410.1016/j.coph.2016.07.014 ↗

7. 10.1016/j.coviro.2013.06.01410.1016/j.coviro.2013.06.014 ↗

8. 10.1016/j.bbrc.2007.02.04410.1016/j.bbrc.2007.02.044 ↗

9. 10.1155/2013/89051710.1155/2013/890517 ↗

10. 10.1016/j.jhep.2020.09.02210.1016/j.jhep.2020.09.022 ↗

11. 10.1074/jbc.M70792820010.1074/jbc.M707928200 ↗

12. 10.1158/0008-5472.CAN-12-279510.1158/0008-5472.CAN-12-2795 ↗

13. Shih‐Hsien Hsu L.‐T. W. · Cancer Res. · 2012 · 2012

14. 10.15252/embr.20194879510.15252/embr.201948795 ↗

15. 10.1158/0008-5472.CAN-17-009010.1158/0008-5472.CAN-17-0090 ↗

16. Sun H. Y. · Cell. Microbiol. · 2017 · 19 · 1

17. 10.1016/j.canlet.2021.07.01110.1016/j.canlet.2021.07.011 ↗

18. 10.1007/s00281-012-0356-210.1007/s00281-012-0356-2 ↗

19. 10.3748/wjg.v22.i4.146110.3748/wjg.v22.i4.1461 ↗

20. 10.1093/carcin/bgz13210.1093/carcin/bgz132 ↗

21. 10.1038/emm.2005.1910.1038/emm.2005.19 ↗

22. 10.1111/jvh.1267510.1111/jvh.12675 ↗

23. 10.1074/jbc.M00667120010.1074/jbc.M006671200 ↗

24. 10.1096/fj.01-021710.1096/fj.01-0217 ↗

25. 10.1136/gut.2005.07041710.1136/gut.2005.070417 ↗

26. 10.1016/j.bbadis.2015.02.00110.1016/j.bbadis.2015.02.001 ↗

27. Oxenkrug G. · Endocrinol. Diabetes Metab. J. · 2017 · 103 · 1077

28. 10.1089/met.2017.009710.1089/met.2017.0097 ↗

29. 10.3389/fimmu.2017.0119510.3389/fimmu.2017.01195 ↗

30. 10.1007/s00011-017-1029-310.1007/s00011-017-1029-3 ↗

31. 10.3389/fimmu.2019.0147010.3389/fimmu.2019.01470 ↗

32. 10.1007/s12026-015-8680-y10.1007/s12026-015-8680-y ↗

33. 10.3389/fimmu.2021.69086910.3389/fimmu.2021.690869 ↗

34. 10.1007/s00432-019-02879-210.1007/s00432-019-02879-2 ↗

35. 10.1038/nature1049110.1038/nature10491 ↗

36. 10.3389/fimmu.2020.0038810.3389/fimmu.2020.00388 ↗

37. 10.1158/1078-0432.CCR-18-288210.1158/1078-0432.CCR-18-2882 ↗

38. 10.1002/jmv.2508310.1002/jmv.25083 ↗

39. 10.1371/journal.ppat.100348610.1371/journal.ppat.1003486 ↗

40. 10.3389/fcell.2020.0066110.3389/fcell.2020.00661 ↗

41. 10.3390/ijms2018456910.3390/ijms20184569 ↗

42. 10.1093/carcin/bgu16610.1093/carcin/bgu166 ↗

43. Ada E. S. · Curr. Protoc. Immunol. · 2004 · 3 · 1

44. 10.1038/s41467-020-15997-010.1038/s41467-020-15997-0 ↗

45. 10.1007/BF0247157610.1007/BF02471576 ↗