The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells.
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.
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.|Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Abigail D G
AD
Nunn
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.|Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Tullio
T
Scopigno
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291-293, 00161 Rome, Italy.
Natalia
N
Pediconi
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.|Department of Internal Medicine, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.|INSERM U1052- Cancer Research Center of Lyon (CRCL), 151 Cours Albert Thomas, 69008 Lyon, France.|Department of Hepatology, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon 69004, France.
Massimo
M
Levrero
Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.
Henning
H
Hagman
Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.
Juris
J
Kiskis
Department of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.
Annika
A
Enejder
D001549:Benzamides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D066292:Lipid Droplets / Q000187:drug effects* / Q000502:physiology; D000073758:Nonlinear Optical Microscopy; D019301:Oleic Acid / Q000494:pharmacology; D000070780:Perilipin-2 / Q000235:genetics / Q000378:metabolism; D000071229:Perilipin-4 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis; D015854:Up-Regulation
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D000070780:Perilipin-2; D000071229:Perilipin-4; D011725:Pyridines; D014280:Triglycerides; C118739:entinostat; D019301:Oleic Acid; D013230:Stearoyl-CoA Desaturase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D006655:Histone Deacetylases