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.

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).

Reviewing Editor

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

Publication 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.

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  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
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