Intracellular & extracellular lipolysis : regulation by the PPAR targets ANGPTL4 & HILPDA

Abstract

The body efficiently stores energy in the form of triglyceride (fat) molecules. However, triglycerides cannot directly enter or exit our cells, but first need to be degraded to so-called fatty acids before moving in or out a cell. This degradation process, called lipolysis, is crucial for human physiology and is tightly regulated to prevent the accumulation of fats either within organs or within the bloodstream - hallmarks of diseases such as obesity and cardiovascular disease. To allow for uptake by underlying organs, triglycerides in the circulation are efficiently broken down by an enzyme called lipoprotein lipase (LPL) that sits in the bloodstream of multiple organs (extracellular lipolysis). In this thesis, we characterized a protein named angiopoietin-like 4 (ANGPTL4) that potently inhibits LPL and, thereby, inhibits the breakdown of triglycerides in the bloodstream. Our data show that by adjusting the tissue expression levels of ANGPTL4, different organs collaborate to ensure that triglycerides are distributed to organs in need of energy. Moreover, we uncovered that, in the fat tissue, ANGPTL4 starts to inhibit LPL before LPL arrives in the bloodstream. By preventing the arrival of LPL in the bloodstream, ANGPTL4 is capable of rapidly adjusting the rates of triglyceride degradation and the concomitant uptake of fatty acids from the circulation to the energy requirements of the underlying organ. To exit our cells, stored triglycerides, such as present in our fat tissue, need to be broken down to fatty acids. Subsequently, the released fatty acids can fuel other organs in need of energy. To further clarify the mechanisms underlying this process of intracellular lipolysis, we investigated the role of a promising new protein called HILPDA. Our data show, however, that loss of HILPDA did not impact the release of fatty acids from the fat tissue, while a high abundance of HILPDA only had a mild attenuating effect on the release of fatty acids. This suggests that HILPDA is not a major physiological regulator of intracellular lipolysis in fat cells. In conclusion, in this thesis, we have clarified the regulation of intracellular and extracellular lipolysis by studying the respective roles of the proteins ANGPTL4 and HILPDA. Such efforts are clinically relevant, as regulators of lipolysis are potential therapeutic targets to lower cardiovascular disease risk.