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Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

Author

Listed:
  • Mercedes Dávalos-Salas

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine)

  • Magdalene K. Montgomery

    (Department of Physiology, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne)

  • Camilla M. Reehorst

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine)

  • Rebecca Nightingale

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine)

  • Irvin Ng

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine)

  • Holly Anderton

    (Olivia Newton John Cancer Research Institute)

  • Sheren Al-Obaidi

    (Olivia Newton John Cancer Research Institute)

  • Analia Lesmana

    (Olivia Newton John Cancer Research Institute)

  • Cameron M. Scott

    (Olivia Newton John Cancer Research Institute)

  • Paul Ioannidis

    (Olivia Newton John Cancer Research Institute)

  • Hina Kalra

    (La Trobe Institute for Molecular Sciences, La Trobe University)

  • Shivakumar Keerthikumar

    (La Trobe Institute for Molecular Sciences, La Trobe University)

  • Lars Tögel

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine)

  • Angela Rigopoulos

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine)

  • Sylvia J. Gong

    (Olivia Newton John Cancer Research Institute)

  • David S. Williams

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine
    Department of Pathology, Austin Health)

  • Prusoth Yoganantharaja

    (Department of Medicine, Deakin University)

  • Kim Bell-Anderson

    (Faculty of Science, Charles Perkins Centre, University of Sydney)

  • Suresh Mathivanan

    (La Trobe Institute for Molecular Sciences, La Trobe University)

  • Yann Gibert

    (Department of Medicine, Deakin University)

  • Scott Hiebert

    (Vanderbilt University)

  • Andrew M. Scott

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine
    Department of Medicine, University of Melbourne)

  • Matthew J. Watt

    (Department of Physiology, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne)

  • John M. Mariadason

    (Olivia Newton John Cancer Research Institute
    La Trobe University School of Cancer Medicine
    Department of Medicine, University of Melbourne)

Abstract

Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.

Suggested Citation

  • Mercedes Dávalos-Salas & Magdalene K. Montgomery & Camilla M. Reehorst & Rebecca Nightingale & Irvin Ng & Holly Anderton & Sheren Al-Obaidi & Analia Lesmana & Cameron M. Scott & Paul Ioannidis & Hina , 2019. "Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13180-8
    DOI: 10.1038/s41467-019-13180-8
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