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