The role of oxygen in the regulation of cellular cholesterol metabolism

氧在调节细胞胆固醇代谢中的作用

• 批准号: MR/X008118/1
• 负责人: James Nathan
• 金额: $ 57.8万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX008118%2F1
• 关键词: role; oxygen; regulation; cellular; cholesterol

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.

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应对氧气水平的变化。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。胆固醇对细胞至关重要。它被整合到细胞膜中以维持细胞生长和分裂所需的功能，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会导致组织损伤。阻止胆固醇产生的药物，称为他汀类药物，是治疗与胆固醇积聚相关的疾病（如动脉粥样硬化）的最广泛的处方药。然而，调节胆固醇水平对免疫系统的功能很重要，一些癌症显示出改变的胆固醇代谢，这可能有助于它们的生长。膳食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。胆固醇的生成是一个高度耗氧的过程。然而，氧传感通路和胆固醇合成是如何联系起来的还不清楚，但对于适应低氧环境生长和生存的细胞来说一定很重要。该项目将探索这一途径如何在人类细胞中发挥作用，确定所涉及的关键参与者，并确定它如何在细胞中发生改变，例如那些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靶向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组分非常重要。