Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

  1. Jin Rong Ow
  2. Matias J Cadez
  3. Gözde Zafer
  4. Juat Chin Foo
  5. Hong Yu Li
  6. Soumita Ghosh
  7. Heike Wollmann
  8. Amaury Cazenave-Gassiot
  9. Chee Bing Ong
  10. Markus R Wenk
  11. Weiping Han
  12. Hyungwon Choi
  13. Philipp Kaldis  Is a corresponding author
  1. Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
  2. National University of Singapore (NUS), Singapore
  3. Singapore Bioimaging Consortium, Singapore
  4. Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
  5. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
  6. National University of Singapore NUS), Singapore
  7. Lund University, Sweden

Abstract

Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning b-oxidation, reflected by increased acylcarnitines and reduced b-hydroxybutyrate. This led to elevated plasma free fatty acids, which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here we demonstrate that loss of hepatocyte proliferation is not only an outcome but possibly causative for liver pathology.

Data availability

Raw sequencing data is available at NCBI GEO under accession number GSE159498.

The following data sets were generated

Article and author information

Author details

  1. Jin Rong Ow

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7468-691X
  2. Matias J Cadez

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Gözde Zafer

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Juat Chin Foo

    Biochemistry, National University of Singapore (NUS), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Hong Yu Li

    Singapore Bioimaging Consortium, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Soumita Ghosh

    Medicine, National University of Singapore (NUS), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Heike Wollmann

    Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Amaury Cazenave-Gassiot

    Biochemistry, National University of Singapore (NUS), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Chee Bing Ong

    Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  10. Markus R Wenk

    Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  11. Weiping Han

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5023-2104
  12. Hyungwon Choi

    Medicine, National University of Singapore NUS), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6687-3088
  13. Philipp Kaldis

    Clinical Sciences, Lund University, Malmö, Sweden
    For correspondence
    philipp.kaldis@med.lu.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7247-7591

Funding

The work was supported in part by the Faculty of Medicine, Lund University to PK, the Biomedical Research Council, Agency for Science, Technology and Research (A*STAR) to PK and to AC-G and MRW (IAF-ICP I1901E0040); by SINGA (Singapore International Graduate Award) to GZ; by the National Medical Research Council Singapore, NMRC (NMRC/CBRG/0091/2015) to PK; by National Research Foundation Singapore grant (NRF2016-CRP001-103) to PK; by the National Medical Research Council of Singapore (NMRC-CG-M009 to H.C.); by grants from the National University of Singapore via the Life Sciences Institute to JCF; the Swedish Foundation for Strategic Research Dnr IRC15-0067; and Swedish Research Council, Strategic Research Area EXODIAB, Dnr 2009-1039. 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 in accordance to protocols (#171268) approved by the A*STAR Institutional Animal Care and Use Committee (IACUC) based on the National Advisory Committee for Laboratory Animal Research (NACLAR) Guidelines.

Reviewing Editor

  1. David E James, The University of Sydney, Australia

Version history

  1. Received: October 8, 2020
  2. Accepted: December 19, 2020
  3. Accepted Manuscript published: December 21, 2020 (version 1)
  4. Version of Record published: December 29, 2020 (version 2)
  5. Version of Record updated: November 19, 2021 (version 3)

Copyright

© 2020, Ow et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jin Rong Ow
  2. Matias J Cadez
  3. Gözde Zafer
  4. Juat Chin Foo
  5. Hong Yu Li
  6. Soumita Ghosh
  7. Heike Wollmann
  8. Amaury Cazenave-Gassiot
  9. Chee Bing Ong
  10. Markus R Wenk
  11. Weiping Han
  12. Hyungwon Choi
  13. Philipp Kaldis
(2020)
Remodelling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division
eLife 9:e63835.
https://doi.org/10.7554/eLife.63835

Share this article

https://doi.org/10.7554/eLife.63835

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