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- Title
Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity.
- Authors
Dávalos-Salas, Mercedes; Montgomery, Magdalene K.; Reehorst, Camilla M.; Nightingale, Rebecca; Ng, Irvin; Anderton, Holly; Al-Obaidi, Sheren; Lesmana, Analia; Scott, Cameron M.; Ioannidis, Paul; Kalra, Hina; Keerthikumar, Shivakumar; Tögel, Lars; Rigopoulos, Angela; Gong, Sylvia J.; Williams, David S.; Yoganantharaja, Prusoth; Bell-Anderson, Kim; Mathivanan, Suresh; Gibert, Yann
- 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. Histone deacetylase 3 (HDAC3) is a regulator of lipid homeostasis in several tissues, however, its role in intestinal lipid metabolism was not yet known. Here the authors study intestine specific HDAC3 knock out mice and report that these animals have increased fatty acid oxidation and undergo remodeling of the intestinal epithelial cell lipidome.
- Subjects
HISTONE deacetylase; ENTEROCYTES; MICE physiology; OBESITY in animals; LIPID metabolism
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-13180-8