Selected cholesterol biosynthesis inhibitors produce accumulation of the intermediate FF-MAS that targets nucleus and activates LXRα in HepG2 cells

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 physiologicprocesses regulated by nuclear receptors, such as lipid homeostasis and cell proliferation. In this work, weestablished a model to selectively accumulate FF-MAS in HepG2 cells, by using a combination of the inhibitorsAY9944 and 17-hydroxyprogesterone to block C14-sterol reductases and the downstream C4-demethylasecomplex. We investigated the effects produced by altered levels of cholesterol biosynthesis intermediates, inorder to dissect their influence on LXRα signaling. In particular, endogenously accumulated FF-MAS was able tomodulate the expression of key genes in cholesterol metabolism, to activate LXRα nuclear signaling resulting inincreased lipogenesis, and to inhibit HepG2 cells proliferation. Moreover, a fluorescent ester derivative of FFMASlocalized in nuclear lipid droplets, suggesting a role for these organelles in the storage of signaling lipidsinteracting with nuclear partners.