Intravascular lipolysis and cardiometabolic disease: molecular physiology, vascular biology, and therapeutics
- Michael PLOUG, Copenhagen University (BRIC) and Copenhagen University Hospital (Rigshospitalet) (Denmark)
- Alan REMALEY, National Heart, Lung, and Blood Institute, National Institutes of Health (USA)
- Anne BEIGNEUX, University of California, Los Angeles (USA)
- Christer BETSHOLTZ, Karolinska Institutet (Sweden)
- Gabriel BIRRANE, Beth Israel Deaconess Medical Center (USA)
- Loren FONG, University of California, Los Angeles (USA)
- Thomas JØRGENSEN, University of Southern Denmark (SDU) (Denmark)
- Maarja MAE, Uppsala University (Sweden)
- Stephen YOUNG, UCLA David Geffen School of Medicine, Los Angeles (USA)
Our Network, the International Triglyceride Consortium (ITC), will examine mechanisms for plasma triglyceride (TG) metabolism and will create new drugs for lowering plasma TG levels and reducing the risk of coronary heart disease (CHD). Our work is scientifically intriguing because basic mechanisms for TG metabolism have remained mysteries. Our work is medically important because inefficient TG metabolism increases CHD risk. Also, current drugs for lowering TG levels are not “precision targeted” and are not particularly effective.
Our Network will focus on the regulation of a key enzyme, lipoprotein lipase (LPL), in TG metabolism. LPL is secreted by muscle and fat cells and then transported into blood vessels, where it functions to digest TGs in lipoprotein particles (a process called lipolysis). Lipolysis is crucial for delivering TGs to the heart for fuel and to adipose tissue for storage; it also creates the lipoprotein particles that promote CHD. We have three objectives, each focused on mysteries in TG metabolism—and each highly relevant to cardiovascular health and disease. The first objective is to understand how LPL is activated by APOC2, a small protein that is found on lipoprotein particles. We will also study how another plasma protein, APOA5, functions to prevent the destruction of LPL on the inside of blood vessels. We will study how APOC2 and APOA5 interact with partner proteins, and we will use our findings to create new therapies for lowering plasma TG levels and reducing CHD risk. Our second objective is to define the binding sites for LPL inside blood vessels and test whether these binding sites could be limited in human disease, thereby contributing to reduced lipolysis, elevated TG levels, and increased CHD risk. Our third objective is to understand the strategies that nature has used to target LPL to the small blood vessels that are immediately adjacent to muscle and fat cells. Targeting of LPL to small blood vessels facilitates efficient fuel delivery to the heart, skeletal muscle, and adipose tissue.
Our Network is excited by our scientific objectives and the opportunity to create new medical therapies. Each member of our Network is an internationally recognized expert in TG metabolism and/or vascular biology. We have unique reagents, extraordinary technical expertise, refined ideas, and a successful track record of international collaboration. Each of our scientists is very strongly committed to training the next generation of cardiovascular scientists. For that reason, our Network’s impact will persist for decades—far longer than the five years of funding provided by the Leducq Foundation.