Cellular and systemic cholesterol transport in physiology and disease

• Ruth FRIKKE-SCHMIDT, University of Copenhagen (Denmark)
• Michael JUNG, Stephen YOUNG, University of California, Los Angeles (USA)
• Arun RADHAKRISHNAN, UT Southwestern Medical Center, Dallas (USA)
• Howard RIEZMAN, University of Geneva (Switzerland)
• John SCHWABE, University of Leicester (UK)

Elevated blood cholesterol levels play a major role in the development of atherosclerosis, a disease that underlies two of the world’s most pressing public health problems—heart attacks and stroke. Excess blood cholesterol leads to its accumulation in cells within arteries and other tissues in the body. We now understand the functions of a handful of proteins that control blood cholesterol levels, but our understanding of important areas of cholesterol metabolism have remained elusive, in particular how cholesterol moves within cells and tissues. We have assembled a team of accomplished investigators with complementary expertise in cell biology, physiology, structural biology, human genetics, and synthetic medicinal chemistry. We will bring this expertise to bear on a single problem—cholesterol trafficking. Our team, “The Cholesterol Constellation,” is motivated by the conviction that crucial pathways in cholesterol metabolism remain to be discovered and targeted for the prevention of human disease.

Cholesterol is a lipid and cannot be dissolved in water. For that reason, the movement of cholesterol within cells and tissues depends on transporter proteins. Members of our Leducq Network have recently identified a new family of cholesterol transporters and have uncovered new mechanisms for cholesterol movement within cells and out of cells. We will build on these discoveries to develop a roadmap for cholesterol transport within cells and between tissues. We will identify new proteins that transport cholesterol and decipher the molecular signals that govern when and where cholesterol moves. We will also work to better understand cholesterol metabolism at the whole-body level, in particular how perturbations in cholesterol metabolism within cells affect blood cholesterol levels and atherosclerotic disease. We will use the tools of human genetics to investigate the role of cholesterol transporters in cardiovascular disease and other age-related diseases where cholesterol transport may play important roles. Finally, we will identify small molecules that influence the function of cholesterol transporters, with the goal of developing drugs to regulate cholesterol transport and ultimately to lower risk for heart attack and stroke.