Cholesterol is arguably the best-known molecule in the world. It is also a contradictory molecule. On the one hand it is a vital substance playing an important role in organizing cell membranes. At the same time, excess amounts of cholesterol in the form of LDL particles can lead to atherosclerosis and other diseases. Cholesterol has other roles, too. For instance, it is covalently bound to a signaling protein called hedgehog, and cholesterol may have more direct roles in other signaling processes.

Our lab is interested in the question how an organism maintains a healthy balance of cellular cholesterol. How is cholesterol sensed? What are the cellular components that direct increased metabolism, uptake or excretion? A main goal of our lab is to identify new genes involved in these processes and to study their cellular roles.

To address these questions, we are taking a multi-layered approach using the fruit fly as a model system. Drosophila is a well-established model organism for developmental biologists, but a focus on metabolic pathways has only emerged in the recent years. Large parts of the sterol transport and metabolism pathways are conserved between flies and humans, allowing us dissect these pathways in Drosophila.

One of our experimental approaches uses genomics. We have analyzed genome-wide transcriptional changes in wild type animals in response to different levels of dietary cholesterol, which allowed us to identify new genes that are regulated by this substance, but not other fats.

We are also analyzing the effect of mutations on the animals’ ability to respond to cholesterol. We are testing mutations in members of the nuclear receptor superfamily and other transcriptional regulators that appear to control nutrient metabolism. We have identified a Drosophila nuclear receptor that appears to regulate key players in cholesterol pathways such as homologs of human NPC1 and NPC2. These genes encode two entirely different proteins that cause the same disease in humans, Niemann-Pick disease Type C. NPC1 normally facilitates the transport of excess cholesterol out of the cell. However, in NPC patients, intracellular transport fails, and high levels of cholesterol accumulate, leading to the death of the patient in their teenage years.

We are currently studying whether the fly homologs of NPC1 and NPC2 are direct targets of this nuclear receptor, and how their activity is regulated by changing levels of dietary cholesterol.