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

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

Author information

1
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.
2
Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
3
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291-293, 00161 Rome, Italy.
4
Department of Internal Medicine, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
5
INSERM U1052- Cancer Research Center of Lyon (CRCL), 151 Cours Albert Thomas, 69008 Lyon, France.
6
Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon 69004, France.
7
Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.

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.

PMID:
27320682
PMCID:
PMC4913258
DOI:
10.1038/srep28025
[Indexed for MEDLINE]
Free PMC Article

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