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

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 Kalra, Shivakumar Keerthikumar, Lars Tögel, Angela Rigopoulos, Sylvia J. Gong, David S. Williams, Prusoth Yoganantharaja, Kim Bell-Anderson, Suresh Mathivanan, Yann Gibert, Scott Hiebert, Andrew M. Scott, Matthew J. Watt () and John M. Mariadason ()
Additional contact information
Mercedes Dávalos-Salas: Olivia Newton John Cancer Research Institute
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
Rebecca Nightingale: Olivia Newton John Cancer Research Institute
Irvin Ng: Olivia Newton John Cancer Research Institute
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
Angela Rigopoulos: Olivia Newton John Cancer Research Institute
Sylvia J. Gong: Olivia Newton John Cancer Research Institute
David S. Williams: Olivia Newton John Cancer Research Institute
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13180-8

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