Is this idea a Compelling Question (CQ) or Critical Challenge (CC)?
Compelling Question (CQ)
Details on the impact of addressing this CQ or CC
Over the past two years, it has become extremely clear that impaired processing of triglyceride-rich lipoproteins has an enormous impact on the frequency of coronary heart disease. For example, large genetic studies have shown that loss-of-function mutations in the gene for apolipoprotein CIII protect from atherosclerotic heart disease. Equally important is the observation that mutations in the gene for apolipoprotein AV are nearly as important as the LDL receptor as a cause of coronary heart disease.
The fact that plasma triglyceride metabolism is so important for atherosclerotic heart disease has caught the field by surprise. For many years, there was considerable doubt about the importance of plasma triglycerides for atherosclerotic heart disease. These doubts have vanished.
Now, in terms of basic research, the triglyceride metabolism field needs to play "catch up" ball. At this time, we have little understanding of intravascular lipolysis. We don't really know the molecular basis for the effects of apo-CIII, apo-CII, and apo-AV on intravascular lipolysis. The effects of these proteins on the LPL–GPIHBP1 complex are unknown. We don't understand how the lipid products of lipolysis move across capillary endothelial cells. We don't even understand why heparin releases LPL from GPIHBP1, and that observation is more than 60 years old! We don't understand the factors that explain differences in the efficiency of plasma triglyceride metabolism.
Feasibility and challenges of addressing this CQ or CC
I believe that the field is now poised to understand intravascular lipolysis at the molecular level, and to investigate why some individuals have inefficient lipolysis and higher plasma triglyceride levels. Within the past few years, the "cast" of molecules that affect (or regulate) plasma triglyceride metabolism have come into focus. The field is poised for progress.
In part because of long-held doubts about the importance of plasma triglyceride metabolism, reagents for key proteins in intravascular metabolism are not in hand simply not in hand (recombinant proteins, specific antibodies). Developing and distributing these reagents is quite feasible, but it has not yet been accomplished.
Similarly, imaging tools are now available to understand the movement of the fatty acid products of lipolysis to myocytes and adipocytes, but there have been few attempts to use those tools.
We need to understand intravascular metabolism. At this time, no one understands the basics. No one knows how app-CII, app-CIII, and app-AV work. We need to understand how ANGPTL4 and ANGPTL3 regulate lipolysis. We need to understand the biochemistry of the LPL–GPIHBP1 complex. These tasks are feasible but will require hard work from many interested investigators.
In the end, once intravascular lipolysis is better understood, it is highly likely that there will be many new strategies for lowering plasma triglyceride levels and reducing the frequency of coronary heart disease.
Name of idea submitter and other team members who worked on this idea
Stephen G. Young