Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA

  1. Yo Han Lee
  2. Hyun-Jun Jang
  3. Sounkou Kim
  4. Sun Sil Choi
  5. Keon Woo Khim
  6. Hye-Jin Eom
  7. Jimin Hyun
  8. Kyeong Jin Shin
  9. Young Chan Chae
  10. Hongtae Kim
  11. Jiyoung Park
  12. Neung Hwa Park
  13. Chang-Yun Woo
  14. Chung Hwan Hong
  15. Eun Hee Koh
  16. Dougu Nam  Is a corresponding author
  17. Jang Hyun Choi  Is a corresponding author
  1. Ulsan National Institute of Science and Technology, Republic of Korea
  2. Ulsan University Hospital, Republic of Korea
  3. Asan Medical Center, Republic of Korea

Abstract

Background:

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear.

Methods:

Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model.

Results:

We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice.

Conclusions:

Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD.

Funding:

This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE168484. Other data generated or analysed during this study are included in the manuscript. Source data files have been provided.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Yo Han Lee

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3422-0306
  2. Hyun-Jun Jang

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2261-0067
  3. Sounkou Kim

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Sun Sil Choi

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Keon Woo Khim

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Hye-Jin Eom

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Jimin Hyun

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  8. Kyeong Jin Shin

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Young Chan Chae

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. Hongtae Kim

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  11. Jiyoung Park

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3705-4769
  12. Neung Hwa Park

    Department of Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  13. Chang-Yun Woo

    Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  14. Chung Hwan Hong

    Department of Medical Science, Asan Medical Center, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  15. Eun Hee Koh

    Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  16. Dougu Nam

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    For correspondence
    dougnam@unist.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
  17. Jang Hyun Choi

    Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
    For correspondence
    janghchoi@unist.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0526-9028

Funding

National Research Foundation of Korea (2020R1F1A1061267)

  • Jang Hyun Choi

National Research Foundation of Korea (2018R1A5A1024340)

  • Jang Hyun Choi

National Research Foundation of Korea (NRF-2021R1I1A2041463)

  • Jang Hyun Choi

National Research Foundation of Korea (2020R1I1A1A01074940)

  • Hyun-Jun Jang

Korea Mouse Phenotyping Project (2016M3A9D5A01952411)

  • Jang Hyun Choi

Future-leading Project Research Fund (1.210034.01)

  • Jang Hyun Choi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matthew A Quinn, Wake Forest School of Medicine, United States

Ethics

Animal experimentation: All animal experiments were performed according to procedures approved by the Ulsan National Institute of Science and Technology's Institutional Animal Care and Use Committee (UNISTIACUC-19-04).

Human subjects: Human liver tissue samples of 21 patients were acquired from the BioResource Center (BRC) of Asan Medical Center, Seoul, Republic of Korea. The process of 21 human tissue samples was officially approved by the Institutional Review Board of Asan Medical Center (IRB approval number: 2018-1512).

Version history

  1. Received: May 18, 2021
  2. Preprint posted: June 7, 2021 (view preprint)
  3. Accepted: December 24, 2021
  4. Accepted Manuscript published: December 29, 2021 (version 1)
  5. Version of Record published: January 13, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,893
    views
  • 437
    downloads
  • 21
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yo Han Lee
  2. Hyun-Jun Jang
  3. Sounkou Kim
  4. Sun Sil Choi
  5. Keon Woo Khim
  6. Hye-Jin Eom
  7. Jimin Hyun
  8. Kyeong Jin Shin
  9. Young Chan Chae
  10. Hongtae Kim
  11. Jiyoung Park
  12. Neung Hwa Park
  13. Chang-Yun Woo
  14. Chung Hwan Hong
  15. Eun Hee Koh
  16. Dougu Nam
  17. Jang Hyun Choi
(2021)
Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA
eLife 10:e70472.
https://doi.org/10.7554/eLife.70472

Share this article

https://doi.org/10.7554/eLife.70472

Further reading

    1. Cancer Biology
    2. Cell Biology
    Mengya Zhao, Beiying Dai ... Yijun Chen
    Research Article

    Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

    1. Cell Biology
    2. Genetics and Genomics
    Yangzi Zhao, Lijun Ren ... Zhukuan Cheng
    Research Article

    Cohesin is a multi-subunit protein that plays a pivotal role in holding sister chromatids together during cell division. Sister chromatid cohesion 3 (SCC3), constituents of cohesin complex, is highly conserved from yeast to mammals. Since the deletion of individual cohesin subunit always causes lethality, it is difficult to dissect its biological function in both mitosis and meiosis. Here, we obtained scc3 weak mutants using CRISPR-Cas9 system to explore its function during rice mitosis and meiosis. The scc3 weak mutants displayed obvious vegetative defects and complete sterility, underscoring the essential roles of SCC3 in both mitosis and meiosis. SCC3 is localized on chromatin from interphase to prometaphase in mitosis. However, in meiosis, SCC3 acts as an axial element during early prophase I and subsequently situates onto centromeric regions following the disassembly of the synaptonemal complex. The loading of SCC3 onto meiotic chromosomes depends on REC8. scc3 shows severe defects in homologous pairing and synapsis. Consequently, SCC3 functions as an axial element that is essential for maintaining homologous chromosome pairing and synapsis during meiosis.