The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells

Sci Rep. 2016 Jun 20;6:28025. doi: 10.1038/srep28025.

Abstract

Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Line
  • Fatty Acid Synthase, Type I / genetics
  • Fatty Acid Synthase, Type I / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Image Processing, Computer-Assisted
  • Lipid Droplets / drug effects*
  • Lipid Droplets / physiology
  • Nonlinear Optical Microscopy
  • Oleic Acid / pharmacology
  • Perilipin-2 / genetics
  • Perilipin-2 / metabolism
  • Perilipin-4 / genetics
  • Perilipin-4 / metabolism
  • Pyridines / pharmacology*
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / metabolism
  • Triglycerides / biosynthesis
  • Up-Regulation

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Perilipin-2
  • Perilipin-4
  • Pyridines
  • Triglycerides
  • entinostat
  • Oleic Acid
  • Stearoyl-CoA Desaturase
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Histone Deacetylases