Department of Science, University Roma Tre, Rome, Italy.
Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy.
J Cell Biochem. 2024 Oct;125(10):e30645. doi: 10.1002/jcb.30645. Epub 2024 Sep 20.
Extensive research has focused on cellular cholesterol and its regulation, primarily due to its crucial physiological roles and its association with numerous diseases resulting from dysregulated homeostasis. Consequently, investigating cholesterol metabolism and the network of regulating proteins remains an ongoing challenge for biomedical research seeking new molecular targets to manage aberrant cholesterol levels in pathologic conditions. There is evidence that Sigma-2/TMEM97 receptor regulates cholesterol metabolism. However, the mechanisms remain incompletely understood to date. Therefore, this study aimed to employ a pharmacological approach based on selective Sigma-2/TMEM97 agonists, rimcazole and siramesine, to uncover the contribution of this receptor to cholesterol homeostasis. Our results indicate that Sigma-2/TMEM97 activation modulates cholesterol uptake by altering key proteins involved in, leading to free cholesterol and neutral lipids accumulation. This sheds light on potential mechanisms implied, contributing a new piece to the intricate puzzle of cholesterol metabolism homeostasis.
大量研究集中于细胞胆固醇及其调控，主要是因为它在生理上具有关键作用，而且与许多由于动态平衡失调而导致的疾病有关。因此，研究胆固醇代谢和调节蛋白网络仍然是生物医学研究的一个持续挑战，目的是寻找新的分子靶点来控制病理条件下异常的胆固醇水平。有证据表明 Sigma-2/TMEM97 受体调节胆固醇代谢。然而，迄今为止，其机制仍不完全清楚。因此，本研究旨在采用基于选择性 Sigma-2/TMEM97 激动剂 rimcazole 和 siramesine 的药理学方法，揭示该受体对胆固醇动态平衡的贡献。我们的结果表明，Sigma-2/TMEM97 的激活通过改变参与的关键蛋白来调节胆固醇摄取，导致游离胆固醇和中性脂质积累。这揭示了所涉及的潜在机制，为胆固醇代谢动态平衡这一复杂谜题增添了新的内容。
