The role of oxygen in the regulation of cellular cholesterol metabolism

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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.