Cholesterol Trafficking: Mechanisms in Health and Disease

Cholesterol is a crucial lipid molecule that serves not only as a building block for cellular membranes but also as a cellular communication molecule essential for the production of steroid hormones. When the balance of cholesterol synthesis, uptake or export is disrupted, serious health conditions can arise. These include metabolic dysfunctionassociated steatotic liver disease, in which fat accumulates in the liver; atherosclerosis, characterized by cholesterol deposits in arterial walls; and certain cancers, where altered cholesterol metabolism can promote tumor growth. Some inherited gene mutations can also cause cholesterol imbalance. A well-known example is the loss of function of the Niemann-Pick C1 protein. Under normal circumstances, this protein facilitates the export of cholesterol from the lysosomes. Lysosomes are essential cellular compartments which degrade and recycle cellular material ensuring the removal of cellular waste. When Niemann-Pick C1 is defective, cholesterol accumulates within lysosomes, causing Niemann-Pick disease type C. This progressive lysosomal storage disorder manifests with a range of neurological symptoms, including cognitive decline and developmental delay. Although several therapies are now available that can slow the progression of Niemann-Pick disease type C, none directly remove the trapped cholesterol from lysosomes. As a result, patients continue to experience cellular dysfunction and disease progression. There is therefore a need to develop treatments that could restore proper cholesterol distribution within cells. The aim of this project is to study how cholesterol leaves the lysosomes and discover novel mechanisms that might be independent of Niemann-Pick C1. In recent years it became clear that the majority of cholesterol transport occurs via non-vesicula transfer between membranes. However, post-lysosomal cholesterol transport remains mainly unexplored. We will use genetic manipulations, bioimaging and biochemical approaches to identify mechanisms of post-lysosomal cholesterol trafficking. By exploring the post-lysosomal cholesterol path, this project will allow for better understanding of cholesterol trafficking and potentially identify novel therapeutic targets that could be used to modulate cellular cholesterol homeostasis and promote lysosomal cholesterol export.