Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

Abstract

The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis.

Facts about Fats: New Insights into the Role of Lipids in Metabolism, Disease and Therapy

“…Even though basic molecular pathways underlying the maintenance of lipid homeostasis are now well established, several regulatory mechanisms still remain unknown. In this context, the experimental work provided by Tonini and colleagues report a novel epigenetic pathway by which cells physiologically control lipid homeostasis [8].…”

“…Even though basic molecular pathways underlying the maintenance of lipid homeostasis are now well established, several regulatory mechanisms still remain unknown. In this context, the experimental work provided by Tonini and colleagues report a novel epigenetic pathway by which cells physiologically control lipid homeostasis [ 8 ]. Notably, the authors unravel that bromodomain and extraterminal domain (BET) proteins, which are epigenetic readers particularly committed to the regulation of cell cycle progression, govern lipid metabolism by modulating the expression of proteins and enzymes implicated in fatty acid and cholesterol biosynthesis, trafficking and uptake.…”

Blocking the Bromodomains Function Contributes to Disturbances in Alga Chara vulgaris Spermatids Differentiation

“…Studies concerning the contribution of bromodomains and their inhibitors to chromatin epigenetic modifications include not only sperm cells but also different cancer cell lines [22,[37][38][39]. The latest research conducted on human hepatocyte carcinoma (Hep G2 cell line) concerned the influence of bromodomain inhibitor JQ1 on lipid homeostasis [40].…”

ProNGF/p75NTR Axis Drives Fiber Type Specification by Inducing the Fast-Glycolytic Phenotype in Mouse Skeletal Muscle Cells

“…Cultured cells and TA muscles from WT and mdx mice were lysed in sample buffer (0.125 M Tris-HCl containing 10% SDS, protease inhibitor cocktail, pH 6.8) by sonication (duty cycle 20%, output 3) as previously described [ 23 , 24 ]. Subsequently, after the addition of the Laemmli buffer and denaturation at 95 °C for 5 min, the samples (twenty micrograms of proteins) were resolved on SDS-PAGE [ 25 ].…”