Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

lncRNA NEAT1 regulates fibrosis and inflammatory response induced by nonalcoholic fatty liver by regulating miR-506/GLI3

  • 4 Accesses

Abstract

Background: As one of the most common liver disorders worldwide, nonalcoholic fatty liver disease (NAFLD) begins with the abnormal accumulation of triglyceride (TG) in the liver and can lead to inflammation and fibrosis. Long noncoding RNA (lncRNA) NEAT1 was reported to promote NAFLD progress. However, its molecular mechanism in NAFLD was not fully clear. Method: In vitro cellular model of NAFLD was established with BRL3A cell treated by free fatty acid (FFA). Cell Counting Kit-8 (CCK-8) assay was carried out to assess cell proliferation. The expression of mRNA and protein of inflammation and fibrosis in BRL3A cell was detected by qRT-PCR and Western blot. Bioinformatics and dual-luciferase reporter assays were used to predict and validate the interaction between NEAT1 and miR-506 as well as GLI3 and miR-506. Results: NEAT1 was upregulated while miR-506 was downregulated in the progression of NAFLD. Meanwhile, NEAT1 and miR-506 were proved to regulate fibrosis, inflammatory response, and lipid metabolism. Knockdown of NEAT1 inhibited GLI3 expression and promoted miR- 506 expression, Overexpression of miR-506 inhibited NEAT1 and GLI3 expression. Moreover, dual-luciferase reporter assays proved that miR-506 could bind to NEAT1 and GLI3, whereas NEAT1 could sponge miR-506 to regulate GLI3 expression. Conclusion: lncRNA NEAT1 could regulate fibrosis, inflammatory response, and lipid metabolism via the miR-506/GLI3 axis as a ceRNA, which is a novel mechanistic role in the regulation of NAFLD. These results provide a new potential treatment target for NAFLD.

This is a preview of subscription content, log in to check access.

Abbreviations

NAFLD:

non-alcoholic fatty liver disease

HCC:

hepatocellular carcinoma

NEAT1:

nuclear enriched abundant transcript 1

lncRNAs:

long non-coding RNAs

qRT-PCR:

quantitative realtime polymerase chain reaction

FFA:

free fatty acid

DMEM:

dulbecco’s modified eagle medium

ACC:

acetyl-CoA carboxylase

CCK-8:

Cell Counting Kit-8

Hh:

hedgehog

ceRNA:

competing endogenous RNA

References

  1. 1.

    Abd El-Kader SM, El-Den Ashmawy EM. Non-alcoholic fatty liver disease: the diagnosis and management. World J Hepatol 2015; 7: 846–58.

  2. 2.

    Argyrou C, Moris D, Vernadakis S. Hepatocellular carcinoma development in non-alcoholic fatty liver disease and nonalcoholic steatohepatitis. Is it going to be the “Plague” of the 21st century? A literature review focusing on pathogenesis, prevention and treatment. J BUON 2017; 22: 6–20.

  3. 3.

    Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 2012; 56: 1384–91.

  4. 4.

    Verdelho Machado M, Diehl AM. The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol 2018; 53: 264–78.

  5. 5.

    Cao J. The functional role of long non-coding RNAs and epigenetics. Biol Proc Online 2014; 16: 11.

  6. 6.

    Serviss JT, Johnsson P, Grander D. An emerging role for long non-coding RNAs in cancer metastasis. Front Genet 2014; 5: 234.

  7. 7.

    Ma H, Han P, Ye W, et al. The long noncoding RNA NEAT1 exerts antihantaviral effects by acting as positive feedback for RIG-I signaling. J Virol 2017; 91: e02250–2316.

  8. 8.

    Zhang M, Weng W, Zhang Q, et al. The lncRNA NEAT1 activates Wnt/beta-catenin signaling and promotes colorectal cancer progression via interacting with DDX5. J Hematol Oncol 2018; 11: 113.

  9. 9.

    Yong W, Yu D, Jun Z, et al. Long noncoding RNA NEAT1, regulated by LIN28B, promotes cell proliferation and migration through sponging miR-506 in high-grade serous ovarian cancer. Cell Death Dis 2018; 9: 861.

  10. 10.

    Han D, Wang J, Cheng G. LncRNA NEAT1 enhances the radio-resistance of cervical cancer via miR-193b-3p/CCND1 axis. Oncotarget 2018; 9: 2395–409.

  11. 11.

    Wang X. Down-regulation of lncRNA-NEAT1 alleviated the non-alcoholic fatty liver disease via mTOR/S6K1 signaling pathway. J Cell Biochem 2018; 119: 1567–74.

  12. 12.

    Ding N, Wu H, Tao T, Peng E. NEAT1 regulates cell proliferation and apoptosis of ovarian cancer by miR-34a-5p/ BCL2. OncoTargets Therap 2017; 10: 4905–15.

  13. 13.

    Tan HY, Wang C, Liu G, Zhou X. Long noncoding RNA NEAT1-modualted miR-506 regulates gastric cancer development through targeting STAT3. J Cell Biochem 2019; 120 (4): 4827–36.

  14. 14.

    Wen SY, Lin Y, Yu YQ, et al. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene 2015; 34: 717–25.

  15. 15.

    Zhang QR, Zhong ZF, Sang W, et al. Comparative comprehension on the anti-rheumatic Chinese herbal medicine Siegesbeckiae Herba: combined computational predictions and experimental investigations. JEthnopharmacol 2019; 228: 200–9.

  16. 16.

    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73–84.

  17. 17.

    Ahmed M. Non-alcoholic fatty liver disease in 2015. World J Hepatol 2015; 7: 1450–9.

  18. 18.

    Basaranoglu M, Basaranoglu G, Senturk H. From fatty liver to fibrosis: a tale of “second hit”. World J Gastroenterol 2013; 19: 1158–65.

  19. 19.

    Hijona E, Hijona L, Arenas JI, Bujanda L. Inflammatory mediators of hepatic steatosis. Mediators Inflamm 2010; 2010: 837419.

  20. 20.

    Perry RB, Ulitsky I. The functions of long noncoding RNAs in development and stem cells. Development 2016; 143: 3882–94.

  21. 21.

    Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature 2014; 505: 344–52.

  22. 22.

    Xie Q, Lin S, Zheng M, Cai Q, Tu Y. Long noncoding RNA NEAT1 promoted the growth of cervical cancer cells via sponging miR-9-5p. Biochem Cell Biol 2019; 97(2):100–8.

  23. 23.

    Tu J, Zhao Z, Xu M, Lu X, Chang L, Ji J. NEAT1 upregulates TGF-beta1 to induce hepatocellular carcinoma progression by sponging hsa-mir-139-5p. J Cell Physiol 2018; 233: 8578–87.

  24. 24.

    Zhang XN, Zhou J, Lu XJ. The long noncoding RNA NEAT1 contributes to hepatocellular carcinoma development by sponging miR-485 and enhancing the expression of the STAT3. J Cell Physiol 2018; 233: 6733–41.

Download references

Acknowledgments

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Author information

Correspondence to Hua-Qin Guan.

Additional information

Conflict of Interest

The authors declare that there are no conflicts of interest.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jin, S., Lin, X., Zheng, J. et al. lncRNA NEAT1 regulates fibrosis and inflammatory response induced by nonalcoholic fatty liver by regulating miR-506/GLI3. Eur Cytokine Netw 30, 98–106 (2019). https://doi.org/10.1684/ecn.2019.0432

Download citation

Key words

  • NAFLD
  • lncRNA-NEAT1
  • miR-506
  • GLI3