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.

Details

Title
Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity
Author
Dávalos-Salas, Mercedes 1   VIAFID ORCID Logo  ; Montgomery, Magdalene K 2 ; Reehorst, Camilla M 1   VIAFID ORCID Logo  ; Nightingale, Rebecca 1 ; Ng, Irvin 1   VIAFID ORCID Logo  ; Anderton, Holly 3   VIAFID ORCID Logo  ; Al-Obaidi, Sheren 3 ; Lesmana, Analia 3 ; Scott, Cameron M 3 ; Ioannidis, Paul 3   VIAFID ORCID Logo  ; Kalra, Hina 4 ; Keerthikumar, Shivakumar 4 ; Tögel, Lars 1   VIAFID ORCID Logo  ; Rigopoulos, Angela 1 ; Gong, Sylvia J 3 ; Williams, David S 5 ; Yoganantharaja, Prusoth 6 ; Bell-Anderson, Kim 7   VIAFID ORCID Logo  ; Mathivanan, Suresh 4   VIAFID ORCID Logo  ; Gibert, Yann 6 ; Hiebert, Scott 8 ; Scott, Andrew M 9 ; Watt, Matthew J 2 ; Mariadason, John M 9   VIAFID ORCID Logo 

1  Olivia Newton John Cancer Research Institute, Melbourne, Victoria, Australia; La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia 
2  Department of Physiology, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia 
3  Olivia Newton John Cancer Research Institute, Melbourne, Victoria, Australia 
4  La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Victoria, Australia 
5  Olivia Newton John Cancer Research Institute, Melbourne, Victoria, Australia; La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; Department of Pathology, Austin Health, Melbourne, Victoria, Australia 
6  Department of Medicine, Deakin University, Geelong, Victoria, Australia 
7  Faculty of Science, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia 
8  Vanderbilt University, Nashville, TN, USA 
9  Olivia Newton John Cancer Research Institute, Melbourne, Victoria, Australia; La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia 
Pages
1-14
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13180-8
ProQuest document ID
2317037582
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.