Elevated serum triglycerides are associated with increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is a secreted enzyme that clears lipids from the blood by hydrolyzing the triglycerides component of circulating lipoproteins. LPL has a number of macromolecular inhibitors. In human populations, known mutations in these macromolecular inhibitors result in reduced ability to inhibit LPL. As a result, LPL activity is increased and serum triglycerides are decreased. We recently discovered that one of these proteins, ANGPTL4, acts as a reversible, noncompetitive LPL inhibitor rather than an unfolding molecular chaperone as was previously believed. This new understanding of ANGPTL4 function led us to ask if other LPL inhibitors act on LPL using a similar mechanism. This proposal focuses on biochemically defining the LPL/inhibitor interaction.
In Aim 1 we will define the sequence motifs and kinetic and molecular mechanisms used by these inhibitors to reduce LPL activity.
In Aim 2, we will identify the features on LPL that are recognized by the inhibitors.
In Aim 3 we ask why a variant of LPL has enhanced activity in vivo. To achieve these aims we will combine protein biochemistry, structural proteomics and single molecule TIRF microscopy. Successful completion of these aims will provide a precise molecular understanding of the mechanism of LPL activity and regulation. Because of LPL's key role in human triglyceride metabolism, these discoveries hold promise for developing new therapies for hypertriglyceridemia.
Elevated serum triglycerides affect a third of Americans and are associated with increased risk for heart disease. This project aims to uncover how lipoprotein lipase, the enzyme that clears the fat from the blood, is regulated. Answering this question could suggest new interventions to treat elevated lipid levels in the blood.
|Hayne, Cassandra K; Yumerefendi, Hayretin; Cao, Lin et al. (2018) We FRET so You Don't Have To: New Models of the Lipoprotein Lipase Dimer. Biochemistry 57:241-254|
|Wu, Ming Jing; Wolska, Anna; Roberts, Benjamin S et al. (2018) Coexpression of novel furin-resistant LPL variants with lipase maturation factor 1 enhances LPL secretion and activity. J Lipid Res 59:2456-2465|
|Hayne, Cassandra K; Lafferty, Michael J; Eglinger, Brian J et al. (2017) Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake. Biochemistry 56:525-533|