1. Selected cholesterol biosynthesis inhibitors produce accumulation of the intermediate FF-MAS that targets nucleus and activates LXRα in HepG2 cells.
- Author
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Gatticchi, Leonardo, Cerra, Bruno, Scarpelli, Paolo, Macchioni, Lara, Sebastiani, Bartolomeo, Gioiello, Antimo, and Roberti, Rita
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STEROLS , *CHOLESTEROL , *BIOSYNTHESIS , *MEIOSIS , *HOMEOSTASIS , *HYDROXYPROGESTERONE , *CELL proliferation - Abstract
Sterol intermediates of the cholesterol biosynthetic pathway have drawn attention for novel biological activities. Follicular fluid meiosis activating sterol (FF-MAS) is a LXRα ligand and a potential modulator of physiologic processes regulated by nuclear receptors, such as lipid homeostasis and cell proliferation. In this work, we established a model to selectively accumulate FF-MAS in HepG2 cells, by using a combination of the inhibitors AY9944 and 17-hydroxyprogesterone to block C14-sterol reductases and the downstream C4-demethylase complex. We investigated the effects produced by altered levels of cholesterol biosynthesis intermediates, in order to dissect their influence on LXRα signaling. In particular, endogenously accumulated FF-MAS was able to modulate the expression of key genes in cholesterol metabolism, to activate LXRα nuclear signaling resulting in increased lipogenesis, and to inhibit HepG2 cells proliferation. Moreover, a fluorescent ester derivative of FF-MAS localized in nuclear lipid droplets, suggesting a role for these organelles in the storage of signaling lipids interacting with nuclear partners. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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