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

Salas, Mercedes Davalos; Montgomery, MK; Reehorst, Camilla Marstrander; Nightingale, Rebecca; Ng, Irvin; Anderton, H; Al-Obaidi, S; Lesmana, Analia; Scott, Cameron; Ioannidis, P; Kalra, Hina; Keerthikumar, Shivakumar; Togel, Lars; Rigopoulos, Angela; Gong, Sylvia; Williams, David; Yoganantharaja, P; Bell-Anderson, K; Mathivanan, Suresh; Gibert, Y; Hiebert, S; Scott, Andrew; Watt, MJ; Mariadason, John

doi:10.1038/s41467-019-13180-8

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

journal contribution

posted on 2025-01-14, 01:06 authored by Mercedes Davalos Salas, MK Montgomery, Camilla Marstrander ReehorstCamilla Marstrander Reehorst, Rebecca NightingaleRebecca Nightingale, Irvin Ng, H Anderton, S Al-Obaidi, Analia Lesmana, Cameron Scott, P Ioannidis, Hina Kalra, Shivakumar KeerthikumarShivakumar Keerthikumar, Lars Togel, Angela RigopoulosAngela Rigopoulos, Sylvia GongSylvia Gong, David WilliamsDavid Williams, P Yoganantharaja, K Bell-Anderson, Suresh MathivananSuresh Mathivanan, Y Gibert, S Hiebert, Andrew ScottAndrew Scott, MJ Watt, John MariadasonJohn Mariadason

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.

Funding

This project was supported by NHMRC project grant (GNT1107836), NHMRC Senior Research Fellowships to J.M.M. (GNT1046092) and M.J.W. (GNT1077703), and the Operational Infrastructure Support Program, Victorian Government, Australia.

History

Publication Date

2019-11-22

Journal

Nature Communications

Volume

10

Article Number

5291

Pagination

14p.

Publisher

Springer Nature

ISSN

2041-1723

Rights Statement

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