Mechanism of Intracellular ANGPTL3 and ANGPTL8 Trafficking

Abstract Lipids circulate in the blood in lipoproteins including chylomicrons and very low-density lipoproteins (VLDLs). Lipoprotein Lipase (LPL) is the main enzyme that hydrolyzes the triglycerides from circulating lipoproteins into free fatty acids that can be taken up by cells. Without LPL, dangerously high levels of lipoproteins circulate in the blood, which can lead to cardiovascular disease, amongst other diseases. LPL inhibitors, known as angiopoietin-like (ANGPTL) proteins have key roles in the regulation of lipid metabolism. ANGPTL3 is a potent inhibitor of LPL. ANGPTL8 can form a complex with ANGPTL3 which results in even greater inhibition of LPL. ANGPTL8 is only found in the bloodstream in complex with ANGPTL3. However, where this complex forms, and why ANGPTL8 requires ANGPTL3 for secretion remains a mystery. This proposal aims to understand why ANGPTL8 is unstable when it is not in a complex with ANGPTL3, as well as visualizing the ANGPTL3/8 complex trafficking dynamics.