Skip to main content
SpringerLink
Log in

LncRNA Tug1 relieves the steatosis of SelenoF-knockout hepatocytes via sponging miR-1934-3p

  • Research
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract 

Metabolic dysfunction associated with fatty liver disease (MAFLD), always accompanied by disturbance of glucose and lipid metabolism, is becoming the most difficult obstacle in the next decades. In the current research, we uncover that the potent non-coding RNA Tug1, which is related to metabolic enzymes, regulates hepatocytes steatosis induced by sodium palmitate via miR-1934-3p absorbing. The knockdown of lncRNA-Tug1 distinctly rescues the increased expression level of glycolytic enzymes and fatty acid synthetase via releasing more mature miR-1934-3p in hepatocytes. Moreover, miR-1934-3p suppresses Selenoprotein F (SelenoF) through binding with the SelenoF 3′UTR effectors; importantly, we demonstrated that the deletion of SelenoF consistent with the lncRNA-Tug1’s effecting on metabolism enzymes. In the current paper, the interaction of Tug1/miR-1934-3p/SelenoF was verified by the dual-luciferase reporter system, and IRS1/AKT pathway possesses the essential role in glucolipid metabolism when SelenoF is deleted. We concluded that lncRNA Tug1 functioned as ceRNA to alleviate steatosis and glycolysis in hepatocytes of C57BL/6 through adsorbing miR-1934-3p to release SelenoF and triggering IRS/AKT pathway.

Graphical Abstract

  • The Tug1/miR-1934-3p/SelenoF constructed the ceRNA interact network

  • Selenoprotein F accelerates glucolipid metabolism via IRS1/AKT pathway

  • SelenoF-/- alleviates steatosis in mice liver

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The bioinformatics analysis net could be accessed in the follows: http://starbase.sysu.edu.cn/index.php, http://www.targetscan.org/. The datasets generated during the current study are not publicly available, but the datasets (including part of the biological materials) are available from the corresponding author on reasonable request.

References

  • Chen M, et al. Long noncoding RNA TUG1 aggravates cerebral ischemia/reperfusion injury by acting as a ceRNA for miR-3072-3p to target St8sia2. Oxidative Med Cell Longev. 2022;2022:9381203.

    Google Scholar 

  • Clayton M, et al. From NAFLD to MAFLD: nurse and allied health perspective. Liver Int. 2021;41(4):683–91.

    Article  CAS  PubMed  Google Scholar 

  • Coassolo S, et al. Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation. Nat Commun. 2021;12(1):1718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dubois V, et al. Distinct but complementary contributions of PPAR isotypes to energy homeostasis. J Clin Invest. 2017;127(4):1202–14.

    Article  PubMed  PubMed Central  Google Scholar 

  • Feng X, et al. Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol. 2017;136:136–49.

    Article  CAS  PubMed  Google Scholar 

  • Festuccia WT, et al. PPARgamma agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control. Diabetologia. 2006;49(10):2427–36.

    Article  CAS  PubMed  Google Scholar 

  • Ge Q, et al. MicroRNAs regulated by adiponectin as novel targets for controlling adipose tissue inflammation. Endocrinology. 2012;153(11):5285–96.

    Article  CAS  PubMed  Google Scholar 

  • Ghaboura N, et al. Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3β signaling. Basic Res Cardiol. 2011;106(1):147–62.

    Article  CAS  PubMed  Google Scholar 

  • Gladyshev VN, et al. A new human selenium-containing protein. Purification, characterization, and cDNA sequence. J Biol Chem. 1998;273(15):8910–5.

    Article  CAS  PubMed  Google Scholar 

  • Gu L, et al. The IKKβ-USP30-ACLY axis controls lipogenesis and tumorigenesis. Hepatology. 2021;73(1):160–74.

    Article  CAS  PubMed  Google Scholar 

  • Guo L, et al. Enhanced acetylation of ATP-citrate lyase promotes the progression of nonalcoholic fatty liver disease. J Biol Chem. 2019;294(31):11805–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Z, et al. Interfering TUG1 Attenuates cerebrovascular endothelial apoptosis and inflammatory injury after cerebral ischemia/reperfusion via TUG1/miR-410/FOXO3 ceRNA axis. Neurotox Res. 2022;40(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  • Hu C, et al. Long non-coding RNA NORAD promotes the prostate cancer cell extracellular vesicle release via microRNA-541-3p-regulated PKM2 to induce bone metastasis of prostate cancer. J Exp Clin Cancer Res. 2021;40(1):98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Q, et al. MALAT1 sponges miR-26a and miR-26b to regulate endothelial cell angiogenesis via PFKFB3-driven glycolysis in early-onset preeclampsia. Mol Ther Nucleic Acids. 2021;23:897–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, et al. TUG1 enhances high glucose-impaired endothelial progenitor cell function via miR-29c-3p/PDGF-BB/Wnt signaling. Stem Cell Res Ther. 2020;11(1):441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, et al. miR-1934, downregulated in obesity, protects against low-grade inflammation in adipocytes. Mol Cell Endocrinol. 2016;428:109–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, et al. LncIRS1 controls muscle atrophy via sponging miR-15 family to activate IGF1-PI3K/AKT pathway. J Cachexia Sarcopenia Muscle. 2019;10(2):391–410.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lund Winther A, et al. ANGPTL4 sensitizes lipoprotein lipase to PCSK3 cleavage by catalyzing its unfolding. J Lipid Res. 2021;62:100071.

    Article  CAS  PubMed  Google Scholar 

  • Martinez Calejman C, et al. mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat Commun. 2020;11(1):575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mundi MS, et al. Evolution of NAFLD and its management. Nutr Clin Pract. 2020;35(1):72–84.

    Article  PubMed  Google Scholar 

  • Pike LS, et al. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta-Bioenerg. 2011;1807(6):726–34.

    Article  CAS  Google Scholar 

  • Puckett D, et al. The role of PKM2 in metabolic reprogramming: insights into the regulatory roles of non-coding RNAs. Int J Mol Sci. 2021;22(3):1171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qi W, et al. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med. 2017;23(6):753–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy SS, Agarwal H, Barthwal MK. Cilostazol ameliorates heart failure with preserved ejection fraction and diastolic dysfunction in obese and non-obese hypertensive mice. J Mol Cell Cardiol. 2018;123:46–57.

    Article  CAS  PubMed  Google Scholar 

  • Shang A, et al. Knockdown of long noncoding RNA PVT1 suppresses cell proliferation and invasion of colorectal cancer via upregulation of microRNA-214-3p. Am J Physiol Gastrointest Liver Physiol. 2019;317(2):G222–32.

    Article  CAS  PubMed  Google Scholar 

  • Sohel MMH. Macronutrient modulation of mRNA and microRNA function in animals: a review. Anim Nutr. 2020;6(3):258–68.

    Article  PubMed  PubMed Central  Google Scholar 

  • Steinbrenner H. Interference of selenium and selenoproteins with the insulin-regulated carbohydrate and lipid metabolism. Free Radic Biol Med. 2013a;65:1538–47.

    Article  CAS  PubMed  Google Scholar 

  • Steinbrenner H, Duntas LH, Rayman MP. The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities. Redox Biol. 2022;50:102236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinbrenner H, et al. High selenium intake and increased diabetes risk: experimental evidence for interplay between selenium and carbohydrate metabolism. J Clin Biochem Nutr. 2011;48(1):40–5.

    Article  CAS  PubMed  Google Scholar 

  • Sun L, et al. Long noncoding RNAs regulate adipogenesis. Proc Natl Acad Sci USA. 2013;110(9):3387–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun YZ, et al. Anti-atherosclerotic effect of hesperidin in LDLr(-/-) mice and its possible mechanism. Eur J Pharmacol. 2017;815:109–17.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, et al. The lncRNA ZFAS1 regulates lipogenesis in colorectal cancer by binding polyadenylate-binding protein 2 to stabilize SREBP1 mRNA. Mol Ther Nucleic Acids. 2022;27:363–74.

    Article  CAS  PubMed  Google Scholar 

  • Wang S, et al. Novel insights of dietary polyphenols and obesity. J Nutr Biochem. 2014;25(1):1–18.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xiong Y, et al. Icaritin ameliorates hepatic steatosis via promoting fatty acid β-oxidation and insulin sensitivity. Life Sci. 2021;268:119000.

    Article  CAS  PubMed  Google Scholar 

  • Xu M, et al. iRhom2 promotes hepatic steatosis by activating MAP3K7-dependent pathway. Hepatology. 2020a;73:1346–64.

    Article  Google Scholar 

  • Xu F, et al. Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH. Redox Biol. 2020b;36:101634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan L, Liu G, Wu X. The umbilical cord mesenchymal stem cell-derived exosomal lncRNA H19 improves osteochondral activity through miR-29b-3p/FoxO3 axis. Clin Transl Med. 2021;11(1):e255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yim SH, et al. Role of SelenoF as a gatekeeper of secreted disulfide-rich glycoproteins. Cell Rep. 2018;23(5):1387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin DD, et al. Downregulation of lncRNA TUG1 affects apoptosis and insulin secretion in mouse pancreatic β cells. Cell Physiol Biochem. 2015;35(5):1892–904.

    Article  CAS  PubMed  Google Scholar 

  • Zhang B, et al. Silencing of the lncRNA TUG1 attenuates the epithelial-mesenchymal transition of renal tubular epithelial cells by sponging miR-141-3p via regulating β-catenin. Am J Physiol Ren Physiol. 2020;319(6):F1125–f1134.

    Article  CAS  Google Scholar 

  • Zhang Q, et al. Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pac J Cancer Prev. 2013;14(4):2311–5.

    Article  PubMed  Google Scholar 

  • Zhang S, et al. Regulation of mTORC1 by amino acids in mammalian cells: a general picture of recent advances. Anim Nutr. 2021;7(4):1009–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, et al. Interrogation of nonconserved human adipose lincRNAs identifies a regulatory role of linc-ADAL in adipocyte metabolism. Sci Transl Med. 2018;10(446):eaar5987.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zheng X, et al. Hepatic proteomic analysis of selenoprotein F knockout mice by iTRAQ: an implication for the roles of selenoprotein F in metabolism and diseases. J Proteome. 2020;215:103653.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (General Program, 30871902). Joint Funds of the National Natural Science Foundation of China (Grant No. U22A20524). The key program of the Natural Science Foundation of Heilongjiang Province, China (LH 2022C042).

Author information

Authors and Affiliations

  1. College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, 310000, People’s Republic of China

    Wei Wang

  2. College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, 150030, People’s Republic of China

    Wei Wang, Zhiruo Miao, Xue Qi, Bing Wang, Qingqing Liu, Xu Shi & Shiwen Xu

  3. Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People’s Republic of China

    Shiwen Xu

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiruo Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xue Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qingqing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xu Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shiwen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Wei Wang, Shiwen Xu (funding received)

Methodology: Wei Wang, Zhiruo Miao, Shiwen Xu

Investigation: Wei Wang, Zhiruo Miao

Visualization: Wei Wang, Zhiruo Miao, Xue Qi, Bin Wang, Qingqing Liu, Xu Shi

Supervision: Shiwen Xu

Writing—original draft: Wei Wang

Writing—review & editing: Wei Wang, Shiwen Xu

Corresponding author

Correspondence to Shiwen Xu.

Ethics declarations

Ethics approval and consent to participate

The experiments were approved by the Institutional Animal Care and Use Committee of the Northeast Agricultural University (SRM-06). There is no participant in the whole experiment.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

All authors have read the manuscript and agreed to submit it in its current form for consideration for publication in the Journal.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Miao, Z., Qi, X. et al. LncRNA Tug1 relieves the steatosis of SelenoF-knockout hepatocytes via sponging miR-1934-3p. Cell Biol Toxicol 39, 3175–3195 (2023). https://doi.org/10.1007/s10565-023-09826-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-023-09826-5

Keywords

Search

Navigation