Gill Saloni, Chow Renee, Brown Andrew J
BABS, School of Biotechnology and Biomolecular Sciences, Biosciences, Building D26, University of New South Wales, Sydney, NSW 2052, Australia.
Prog Lipid Res. 2008 Nov;47(6):391-404. doi: 10.1016/j.plipres.2008.04.002. Epub 2008 May 6.
This review traces the evolution of the 'Oxysterol Hypothesis', which was first formulated by Kandutsch and colleagues in 1978. The original hypothesis asserted that the suppressive effect of cholesterol on its own synthesis is mediated not by cholesterol itself, but by oxygenated forms of cholesterol, so called oxysterols. Subsequently, it has become clear that cholesterol plays a pivotal role in its own feedback regulation. However, recent findings have rekindled interest in oxysterols as potential physiological regulators of cholesterol homeostasis, in addition to drawing attention to other sterol regulators. Thus, certain oxysterols can suppress the activation of the master transcriptional regulators of lipid homeostasis (SREBPs) by binding to an oxysterol sensing protein in the Endoplasmic Reticulum (Insig). Some (oxy)sterols can accelerate the degradation of the key cholesterol biosynthetic enzyme, HMG-CoA reductase, and/or serve as natural ligand activators of a nuclear receptor (LXR) involved in coordinating many aspects of reverse cholesterol transport. Recent studies on endogenously produced oxysterols indicate that they may play a more subtle and acute role than originally envisaged, smoothing cholesterol responses in the short term. We also review the metabolism of oxysterols and other recent findings about oxysterols beyond a purely cholesterol homeostatic context, such as their proposed role in the Hedgehog development pathway.
本综述追溯了“氧化甾醇假说”的演变历程，该假说最初由坎杜奇及其同事于1978年提出。最初的假说认为，胆固醇对其自身合成的抑制作用并非由胆固醇本身介导，而是由胆固醇的氧化形式（即所谓的氧化甾醇）介导。随后，人们清楚地认识到胆固醇在其自身的反馈调节中起着关键作用。然而，最近的研究结果重新引发了人们对氧化甾醇作为胆固醇稳态潜在生理调节因子的兴趣，同时也引起了人们对其他甾醇调节因子的关注。因此，某些氧化甾醇可以通过与内质网中的氧化甾醇传感蛋白（Insig）结合，抑制脂质稳态主要转录调节因子（SREBPs）的激活。一些（氧化）甾醇可以加速关键胆固醇生物合成酶HMG-CoA还原酶的降解，和/或作为参与协调逆向胆固醇转运多个方面的核受体（LXR）的天然配体激活剂。最近关于内源性产生的氧化甾醇的研究表明，它们可能比最初设想的发挥更微妙和急性的作用，在短期内使胆固醇反应更加平稳。我们还综述了氧化甾醇的代谢以及关于氧化甾醇的其他最新研究结果，这些结果超出了单纯的胆固醇稳态范畴，例如它们在刺猬发育途径中所提出的作用。
