The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells
Artikel i vetenskaplig tidskrift, 2016

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.

hepatosteatosis

induction

storage

metabolism

droplets

insulin-resistance

gene-regulation

lysine acetylation

secretion

perilipin family

Science & Technology - Other Topics

Författare

A. D. G. Nunn

Istituto Italiano di Tecnologia

Universita degli Studi di Roma La Sapienza

T. Scopigno

Istituto Italiano di Tecnologia

Universita degli Studi di Roma La Sapienza

N. Pediconi

Universita degli Studi di Roma La Sapienza

M. Levrero

Universita degli Studi di Roma La Sapienza

Clinical and Research Memory Center of Lyon

Istituto Italiano di Tecnologia

Hopital de la Croix-Rousse

Henning Hagman

Molekylär mikroskopi och bioteknik

Juris Kiskis

Chalmers, Biologi och bioteknik, Livsmedelsvetenskap

Annika Enejder

Chalmers, Biologi och bioteknik, Livsmedelsvetenskap

Scientific Reports

2045-2322 (ISSN)

Vol. 6 28025

Ämneskategorier

Biokemi och molekylärbiologi

DOI

10.1038/srep28025

PubMed

27320682