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LncRNA XIST promotes mitochondrial dysfunction of hepatocytes to aggravate hepatic fibrogenesis via miR-539-3p/ADAMTS5 axis

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Abstract

A previous study indicated that long non-coding RNA X-inactive-specific transcript (XIST) promoted ethanol-induced HSCs autophagy and activation. Considering the critical role of HSC activation in hepatic fibrosis, the aim of the present study was to reveal the exact role of XIST in liver fibrosis and its underlying mechanism. The expression of XIST in the liver from CCL4-induced mice and control mice as well as human fibrotic liver tissue and healthy liver tissue was examined. The mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potential (MMP), and mitochondrial morphology were measured to assess the mitochondrial damage. The relationship between XIST and miR-539-3p as well as between miR-539-3p and ADAMTS5 was verified by a dual-luciferase reporter assay. The expression levels of HSCs activation markers were examined by Western blot. The results showed that the XIST was upregulated in fibrotic liver tissue, and overexpression of XIST induced mitochondrial dysfunction in hepatocytes. miR-539-3p directly targeted XIST, and ADAMTS5 mRNA was a downstream target of miR-539-3p. Knockdown of miR-539-3p led to an increased mitochondrial damage in hepatocytes in terms of reduced mitochondrial length, decreased MMP, and increased ROS production. However, the depletion of ADAMTS5 reversed the regulatory effect of XIST on mitochondrial damage in hepatocytes and the activation of HSCs. Our study revealed the critical role of the XIST/miR-539-3p/ADAMTS5 axis in regulating mitochondrial damage in hepatocytes and the activation of HSCs. This study may provide a potential therapeutic strategy for the treatment of liver fibrosis.

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Data availability

All data generated or analyzed during this study are included in this published article.

Code availability

Not applicable.

Abbreviations

ADAMTS5:

A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 5

DAMPs:

Endogenous damage-associated molecular patterns

ECM:

Extracellular matrix

H&E:

Hematoxylin & eosin

HSCs:

Hepatic stellate cells

IHC:

Immunohistochemistry

mtDNA:

Mitochondrial DNA

mtROS:

Reactive oxygen species production in mitochondrial

microRNA:

MiRNA

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

ROS:

Reactive oxygen species

RT-qPCR:

Real-time polymerase chain reaction

α-SMA:

Anti-alpha smooth muscle actin

SOD:

Superoxide dismutase (SOD)

TFAM:

Mitochondrial transcription factor A

TGF-β:

Transforming growth factor beta

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick-end labeling

XIST:

X-inactive-specific transcript

References

  1. Wu X, Zhi F, Lun W, Deng Q, Zhang W (2018) Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis. Int J Mol Med 41(4):1992–2002

    Google Scholar 

  2. Song Y, Liu C, Liu X, Trottier J, Beaudoin M, Zhang L et al (2017) H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule. Hepatology 66(4):1183–1196

    Article  CAS  Google Scholar 

  3. Mitchell C, Robin MA, Mayeuf A, Mahrouf-Yorgov M, Mansouri A, Hamard M et al (2009) Protection against hepatocyte mitochondrial dysfunction delays fibrosis progression in mice. Am J Pathol 175(5):1929–1937

    Article  CAS  Google Scholar 

  4. Hur W, Kang BY, Kim SM, Lee GW, Kim JH, Nam MK et al (2019) Serine protease HtrA2/Omi deficiency impairs mitochondrial homeostasis and promotes hepatic fibrogenesis via activation of hepatic stellate cells. Cells. https://doi.org/10.3390/cells8101119

    Article  Google Scholar 

  5. Trotta MC, Pieretti G, Petrillo F, Alessio N, Hermenean A, Maisto R et al (2020) Resolvin D1 reduces mitochondrial damage to photoreceptors of primary retinal cells exposed to high glucose. J Cell Physiol 235(5):4256–4267

    Article  CAS  Google Scholar 

  6. Wang B, Gao X, Liu B, Li Y, Bai M, Zhang Z et al (2019) Protective effects of curcumin against chronic alcohol-induced liver injury in mice through modulating mitochondrial dysfunction and inhibiting endoplasmic reticulum stress. Food Nutr Res. https://doi.org/10.29219/fnr.v63.3567

    Article  Google Scholar 

  7. Kang JW, Hong JM, Lee SM (2016) Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis. J Pineal Res 60(4):383–393

    Article  CAS  Google Scholar 

  8. Wang H-w, Liu J, Wei S-s, Zhao W-p, Zhu S-q, Zhou B-h (2020) Mitochondrial respiratory chain damage and mitochondrial fusion disorder are involved in liver dysfunction of fluoride-induced mice. Chemosphere 241:125099

    Article  CAS  Google Scholar 

  9. Tsushima K, Bugger H, Wende AR, Soto J, Jenson GA, Tor AR et al (2018) Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ Res 122(1):58–73

    Article  CAS  Google Scholar 

  10. Zhou D, Zhou M, Wang Z, Fu Y, Jia M, Wang X et al (2019) PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell death disease 10(7):524

    Article  Google Scholar 

  11. Yang R, Tonnesseen TI (2019) DAMPs and sterile inflammation in drug hepatotoxicity. Hepatol Int 13(1):42–50

    Article  Google Scholar 

  12. Kong Y, Huang T, Zhang H, Zhang Q, Ren J, Guo X et al (2019) The lncRNA NEAT1/miR-29b/Atg9a axis regulates IGFBPrP1-induced autophagy and activation of mouse hepatic stellate cells. Life Sci 237:116902

    Article  CAS  Google Scholar 

  13. Xie ZY, Wang FF, Xiao ZH, Liu SF, Lai YL, Tang SL (2019) Long noncoding RNA XIST enhances ethanol-induced hepatic stellate cells autophagy and activation via miR-29b/HMGB1 axis. IUBMB Life 71(12):1962–1972

    Article  CAS  Google Scholar 

  14. Wang T, Zhai M, Xu S, Ponnusamy M, Huang Y, Liu CY et al (2020) NFATc3-dependent expression of miR-153-3p promotes mitochondrial fragmentation in cardiac hypertrophy by impairing mitofusin-1 expression. Theranostics 10(2):553–566

    Article  CAS  Google Scholar 

  15. Bourd-Boittin K, Bonnier D, Leyme A, Mari B, Tuffery P, Samson M et al (2011) Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta. Hepatology 54(6):2173–2184

    Article  CAS  Google Scholar 

  16. Bukong TN, Maurice SB, Chahal B, Schaeffer DF, Winwood PJ (2016) Versican: a novel modulator of hepatic fibrosis. Lab Invest 96(3):361–374

    Article  CAS  Google Scholar 

  17. Bauters D, Spincemaille P, Geys L, Cassiman D, Vermeersch P, Bedossa P et al (2016) ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity. Liver Int 36(12):1848–1859

    Article  CAS  Google Scholar 

  18. Zhang K, Han Y, Hu Z, Zhang Z, Shao S, Yao Q et al (2019) SCARNA10, a nuclear-retained long non-coding RNA, promotes liver fibrosis and serves as a potential biomarker. Theranostics 9(12):3622–3638

    Article  CAS  Google Scholar 

  19. Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group Hepatol 24(2):289–293

    CAS  Google Scholar 

  20. Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Gatter KC, Harris AL et al (2005) LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer. J Clin Pathol 58(2):202–206

    Article  CAS  Google Scholar 

  21. Gusdon AM, Chen J, Votyakova TV, Mathews CE (2009) Chapter 24 quantification, localization, and tissue specificities of mouse mitochondrial reactive oxygen species production. Methods Enzymol. https://doi.org/10.1016/S0076-6879(08)04424-8

    Article  Google Scholar 

  22. Chen R, Xia W, Wang S, Xu Y, Ma Z, Xu W et al (2019) Long noncoding RNA SBF2-AS1 is critical for tumorigenesis of early-stage lung adenocarcinoma. Mol Ther Nucleic Acids 16:543–553

    Article  CAS  Google Scholar 

  23. Li Q, Liu J, Meng X, Pang R, Li J (2017) MicroRNA-454 may function as an oncogene via targeting AKT in triple negative breast cancer. J Biol Res (Thessalon) 24:10

    Article  Google Scholar 

  24. Mao L, Liu S, Hu L, Jia L, Wang H, Guo M et al (2018) miR-30 Family: A Promising Regulator in Development and Disease. BioMed Res Int 2018:9623412

    Article  Google Scholar 

  25. Ferrasi AC, Fernandez GJ, Grotto RMT, Silva GF, Goncalves J, Costa MC et al (2020) New LncRNAs in Chronic Hepatitis C progression: from fibrosis to hepatocellular carcinoma. Sci Rep 10(1):9886

    Article  CAS  Google Scholar 

  26. Shen C, Li J (2021) LncRNA XIST silencing protects against sepsis-induced acute liver injury via inhibition of BRD4 expression. Inflammation 44(1):194–205

    Article  CAS  Google Scholar 

  27. Bauters D, Bedossa P, Lijnen HR, Hemmeryckx B (2018) Functional role of ADAMTS5 in adiposity and metabolic health. PLoS ONE. https://doi.org/10.1371/journal.pone.0190595

    Article  Google Scholar 

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Acknowledgements

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Funding

This work was supported by Science and Technology Research Project of Jiangxi Education Department (No. GJJ190793) and Scientific Research Project of Gannan Medical University (No. ZD201804).

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Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital of Gannan Medical University, No. 23 Youth Road, Zhanggong District, Ganzhou, 341000, Jiangxi, People’s Republic of China

    Xiong-Jian Wu, Yuan Xie, Xiao-Xiang Gu, Hai-Yan Zhu & Li-Xing Huang

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  1. Xiong-Jian Wu
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  2. Yuan Xie
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  3. Xiao-Xiang Gu
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  4. Hai-Yan Zhu
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  5. Li-Xing Huang
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Contributions

X-JW contributed to concepts, design, funding acquisition, and supervision. YX contributed to methodology and experimental studies. X-XG contributed to writing- original draft preparation, writing- reviewing, and editing. H-YZ contributed to data acquisition and data analysis. L-XH contributed to experimental studies.

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Correspondence to Xiong-Jian Wu.

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Conflict of interest

No conflict of interest, financial or otherwise, is declared by the authors.

Ethical approval

The study has been approved by the local Ethical Committee of the First Affiliated Hospital of Gannan Medical College. All patients provided written informed consent for the storage of liver tissue samples.

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The informed consent is obtained from study participants.

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11010_2022_4506_MOESM1_ESM.tif

Figure S1. Knockdown of ADAMTS5 did not show any impact on XIST or miR-539-3p expression. The (A) mRNA and (B) protein expressions of ADAMTS5 were measured by RT-PCR or western blot after cells transfected with sh-NC and sh-ADAMTS5. The expressions of (C) XIST and (D) miR-539-3p were measured by RT-PCR after cells transfected with sh-NC or sh-ADAMTS5. **p < 0.01. All data were obtained from at least three replicate experiments. (TIF 472 kb)

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Wu, XJ., Xie, Y., Gu, XX. et al. LncRNA XIST promotes mitochondrial dysfunction of hepatocytes to aggravate hepatic fibrogenesis via miR-539-3p/ADAMTS5 axis. Mol Cell Biochem 478, 291–303 (2023). https://doi.org/10.1007/s11010-022-04506-0

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  • DOI: https://doi.org/10.1007/s11010-022-04506-0

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