Regulation of plasma triglycerides by ANGPTL4 and GPIHBP1

• Main Author: Cushing, Emily Malcolm
• Other Authors: Davies, Brandon S.J.
• Format: Others
• Language: English
• Published: University of Iowa 2018
• Subjects: ANGPTL4; chylomicron; GPIHBP1; LPL; metabolism; triglycerides; Biochemistry
• Online Access: https://ir.uiowa.edu/etd/6399; https://ir.uiowa.edu/cgi/viewcontent.cgi?article=7900&context=etd

The absorption, packaging, and delivery of fat to appropriate peripheral tissues is essential for maintaining metabolic homeostasis, and defects or dysregulation of these processes can contribute to metabolic disorders such as diabetes, obesity, and hyperlipidemia. In the intestine, dietary fat is packaged into triglyceride-rich lipoprotein particles and delivered to peripheral tissues through the circulatory system. Lipolysis of lipoprotein triglycerides requires the enzyme lipoprotein lipase (LPL) and takes place on the luminal surface of capillary endothelial cells. Lipolysis by LPL is regulated in part by two proteins, GPIHBP1 and ANGPTL4. GPIHBP1, a GPI-anchored protein of capillary endothelial cells, is responsible for transporting LPL across endothelial cells to the capillary lumen. Without this transport, LPL becomes mislocalized to the interstitial space and cannot access triglyceride-rich lipoproteins, resulting in severe hypertriglyceridemia. Conversely, ANGPTL4 inhibits LPL and ANGPTL4 deficiency results in increased LPL activity and lower plasma triglyceride levels. Our goal is to understand how the interactions between LPL, GPIHBP1, and ANGPTL4 influence the delivery of triglyceride-derived fatty acids to tissues. In this thesis, I (1) use mouse models to elucidate the function of ANGPTL4 in regulating the clearance of diet-derived fat from plasma, (2) describe a mechanism for GPIHBP1-independent plasma triglyceride clearance observed in mice lacking both GPIHBP1 and ANGPTL4, and (3) propose that this GPIHBP1-independent mechanism is also operative in Gpihbp1–/– mice following a high fat diet challenge. The contributions of this thesis are significant because they close a gap in our knowledge of how and where ANGPTL4 functions, as well as indicating that, when ANGPTL4 is suppressed or absent altogether, a GPIHBP1-independent mechanism can function to clear plasma triglycerides.