Anatomy and Neuroscience - Research Publications

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Author: Keerthikumar, Shivakumar × Author: Mariadason, John × Author: Williams, David × End date: 2020 ×

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    Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity
    Davalos-Salas, M ; Montgomery, MK ; Reehorst, CM ; Nightingale, R ; Ng, I ; Anderton, H ; Al-Obaidi, S ; Lesmana, A ; Scott, CM ; Ioannidis, P ; Kalra, H ; Keerthikumar, S ; Togel, L ; Rigopoulos, A ; Gong, SJ ; Williams, DS ; Yoganantharaja, P ; Bell-Anderson, K ; Mathivanan, S ; Gibert, Y ; Hiebert, S ; Scott, AM ; Watt, MJ ; Mariadason, JM (NATURE PUBLISHING GROUP, 2019-11-22)
    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.