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

2019-11-22

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

Hiebert, Scott

Scott, Andrew M

Watt, Matthew J

Mariadason, John M

Journal Article

0000-0003-0692-5904

0000-0002-8039-3582

0000-0002-1357-4666

0000-0003-3913-9686

0000-0002-1003-7478

0000-0003-0612-6440

0000-0002-7761-3441

0000-0002-7290-5795

0000-0001-9123-7684

0000-0002-6656-295X

10.1038/s41467-019-13180-8

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.

link

Nature Communications 2019; 10(1): 5291

Nature Communications