The role of oxygen in the regulation of cellular cholesterol metabolism

我们体内的所有细胞都必须适应氧气供应的变化，我们已经进化出许多策略来感知和响应氧气水平的变化。这种适应性反应的一个重要结果是为支持细胞生长和膜功能的途径提供燃料，例如胆固醇合成途径。胆固醇是细胞所必需的。它被结合到膜中以维持其功能，这是细胞生长和分裂所必需的，并驱动几种酶和激素的形成。然而，过多的胆固醇是有害的，当它在细胞中积累时，可能会导致组织损伤。阻断胆固醇产生的药物被称为他汀类药物，是治疗与胆固醇积累相关的疾病(如动脉粥样硬化)的最广泛的处方药之一。然而，调节胆固醇水平对发挥作用的免疫系统很重要，一些癌症表现出有助于生长的胆固醇代谢变化。饮食中的胆固醇可以被细胞吸收，但大多数细胞也有能力产生自己的胆固醇。胆固醇的产生是一个耗氧量很大的过程。然而，氧感应通路和胆固醇合成是如何联系在一起的还不清楚，但对于已经适应低氧环境生长和生存的细胞来说，这肯定是重要的。我们发现了一条氧介导的胆固醇合成调节的新途径。该项目将探索这一途径如何在人类细胞中发挥作用，确定参与其中的关键因素，并确定它在细胞中可能如何改变，例如已经适应低氧水平的癌症细胞。了解这一途径对于我们使用现有的针对胆固醇生成的治疗方法以及识别可能形成未来治疗靶点的胆固醇途径的新成分将是重要的。

All cells in our body have to adapt to changes in oxygen availability, and we have evolved many strategies to sense and respond to changes in oxygen levels. An important consequence of this adaptive response is to fuel pathways that support cell growth and membrane function, such as the cholesterol synthesis pathway. Cholesterol is essential for cells. It is incorporated into membranes to maintain their function, required for cells to grow and divide, and drives the formation of several enzymes and hormones. However, too much cholesterol is harmful, and can lead to tissue damage when it accumulates in cells. Drugs that block cholesterol production, termed statins, are some of the most widely prescribed medications to treat conditions associated with cholesterol build up, such as atherosclerosis. However, regulating cholesterol levels is important for a functioning immune system, and some cancers display altered cholesterol metabolism that may help them grow.Dietary cholesterol can be taken up by cells, but most cells also have the capacity to generate their own cholesterol. Generation of cholesterol is a highly oxygen consuming process. However, how oxygen-sensing pathways and cholesterol synthesis are linked is not understood, but must be important for cells that have adapted to grow and survive in low oxygen environments.We have uncovered a novel pathway for oxygen-mediated regulation of cholesterol synthesis. This project will explore how this pathway functions in human cells, identify the key players involved, and the determine how it may be altered in cells, such as those from cancers, which have adapted to low oxygen levels. Understanding this pathway will be important for our use of existing therapies targeting cholesterol generation, as well as identifying new components of the cholesterol pathway that may form the basis of future therapeutic targets.