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

Nat Commun. 2019 Nov 22;10(1):5291. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calorimetry
  • Diet, High-Fat
  • Enterocytes / metabolism*
  • Fatty Acids / metabolism
  • Gene Deletion
  • Gene Expression Regulation
  • Histone Deacetylases / genetics*
  • Intestinal Mucosa / metabolism
  • Lipid Metabolism / genetics*
  • Lipid Peroxidation / genetics
  • Lipidomics
  • Mice
  • Mitochondria / metabolism
  • Obesity / genetics*
  • Peroxisome Proliferator-Activated Receptors / agonists
  • Peroxisome Proliferator-Activated Receptors / genetics
  • Triglycerides / metabolism


  • Fatty Acids
  • Peroxisome Proliferator-Activated Receptors
  • Triglycerides
  • Histone Deacetylases
  • histone deacetylase 3