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  • Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling

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Hepatology
Original research
Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling
  1. Chen-Ting Hung1,
  2. Tung-Hung Su2,3,
  3. Yen-Ting Chen1,
  4. Yueh-Feng Wu4,
  5. You-Tzung Chen5,
  6. Sung-Jan Lin4,6,7,8,
  7. Shuei-Liong Lin3,7,9,10,
  8. Kai-Chien Yang1,3,7,11
  1. 1 Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
  2. 2 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
  3. 3 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  4. 4 Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
  5. 5 Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
  6. 6 Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
  7. 7 Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan
  8. 8 Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan
  9. 9 Graduate Institute and Department of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
  10. 10 Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
  11. 11 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  1. Correspondence to Dr Kai-Chien Yang, Graduate Institute and Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan; kcyang{at}ntu.edu.tw

Abstract

Background and objectives Liver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF.

Design Histological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg , Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO ) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO ) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses.

Results TXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice.

Conclusions ER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.

  • liver cirrhosis
  • hepatic stellate cell
  • gene targeting
  • fibrogenesis
  • apoptosis

Data availability statement

Data are available on reasonable request. All data are available from the corresponding author on reasonable request.

https://doi.org/10.1136/gutjnl-2021-325065

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    Data availability statement

    Data are available on reasonable request. All data are available from the corresponding author on reasonable request.

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    Footnotes

    • Contributors Study conceptualisation and experimental design: C-TH, T-HS and K-CY. Cell and animal studies: C-TH, Y-TC and S-LL, Imaging study support: Y-FW and S-JL. K-CY is responsible for the overall content as guarantor. All authors contributed to manuscript writing and editing.

    • Funding This work was funded by Taiwan Ministry of Science and Technology Grants 108-2314-B-002-199-MY3, 109-2628-B-002-032, 110-2628-B-002-054 (K-CY) and 109-2326-B-002-012-MY3 (T-HS); an Innovative Research Grant from Taiwan National Health Research Institute NHRI-EX109-10936SI (K-CY), a CRC Translational Research Grant IBMS-CRC111-P01 (K-CY), a Translational Medicine Grant AS-TM-109-01-04 (K-CY) and a Grand Challenge Grant AS-GC-110–05 from Academia Sinica, Taiwan; grants from National Taiwan University Hospital NTUH.108-T16, VN108-06, VN109-07, VN110-01, NTUH.108-P04, 108-N4198, 108-S4247, 109-EDN05,110-EDN02, 109-S4576, 110-S4836, 110-T16, 109F005-110-B2, 111-IF0005 (K-CY), grants from the Excellent Translation Medicine Research Projects of National Taiwan University College of Medicine and National Taiwan University Hospital, NSCCMOH-131-41, 109C101-41, 110C101-071(K-CY) and Career Development Grants from National Taiwan University 109L7872, 109L7753, 110L7753 (K-CY).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.