Date of Degree
PhD (Doctor of Philosophy)
Brandon SJ. Davies
Dyslipidemia often accompanies metabolic diseases such as obesity and type II diabetes mellitus and represents a risk factor for cardiovascular disease. Clearance of triglycerides from the plasma is mediated by lipoprotein lipase (LPL), which hydrolyzes the triglycerides in chylomicrons and VLDL, liberating fatty acids for tissue uptake. LPL functions in the capillaries of the heart, adipose tissue, and skeletal muscle where LPL is anchored to the capillary wall by its endothelial cell transporter GPIHBP1. LPL activity is regulated by several factors including three members of the angiopoietin-like (ANGPTL) family–ANGPTL3, ANGPTL4, and ANGPTL8. How these proteins interact with LPL, especially in the physiological context of LPL anchored to endothelial cells by GPIHBP1, has not been well characterized. In my studies of ANGPTL4, I found when LPL is bound to GPIHBP1, it is partially, but not completely, protected from inactivation by ANGPTL4. Inactivation of LPL by ANGPTL4 leads to the dissociation of active LPL dimers into inactive monomers and I found that these monomers have a greatly reduced affinity for GPIHBP1. ANGPTL4 can be cleaved in vivo, separating the N-terminal coiled-coil domain from the C-terminal fibrinogen like-domain. I found the N-terminal domain alone is a much more potent LPL inhibitor than the full-length protein, even though both appear to have similar binding affinities for LPL-GPIHBP1 complexes. When I investigated ANGPTL3, I found ANGPTL3 itself is not a potent inhibitor of LPL at physiological concentrations, and unlike ANGPTL4, cleavage of ANGPTL3 does not improve its ability to inhibit LPL. Instead I found that ANGPTL3 forms a complex with ANGPTL8, a complex that only forms efficiently when the two proteins are co-expressed, and that this complex allows ANGPTL3 to bind and inhibit LPL. My data provide new insights into how ANGPTL proteins regulate LPL activity and the delivery of fat to tissues.
angiopoietin-like protein, chylomicrons, lipid metabolism, LPL, plasma triglycerides
xiii, 126 pages
Includes bibliographical references (pages 106-126).
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