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.
Highlights
The homeostatic regulation of lipid metabolism is essential for the maintenance of key cellular processes involved in a plethora of biological functions
In order to evaluate the putative involvement of bromodomain and extraterminal domain (BET) inhibition on lipid homeostasis, the effect of JQ1 on cellular lipid content was firstly assessed
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Summary
The homeostatic regulation of lipid metabolism is essential for the maintenance of key cellular processes involved in a plethora of biological functions. Hepatic cells are the principal site for lipid biosynthesis, determined by the establishment of a complex series of enzymatic reactions; in particular, 3-hydroxy-3-methylglutaryl Coenzyme A reductase (HMGCR) and Acyl Coenzyme A carboxylase (ACC) represent the key and rate-limiting enzymes for cholesterol and fatty acid synthesis, respectively [7,8] Considering their central role in lipid biosynthesis, both HMGCR and ACC are tightly regulated at both short- and long-term levels. It has been observed that BET inhibition efficiently counteracted plasma low density lipoprotein (LDL) alterations in a mouse model of cancer cachexia [17] Despite this evidence, no studies systematically addressed the involvement of BET proteins in the modulation of the main proteins and enzymes controlling the regulatory machinery of lipid metabolism. The effects induced by BET inhibition were mainly evaluated in HepG2 cell line, a human liver-derived cell culture model widely used to assess lipid homeostasis [28,29,30]
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