During the past 5 years, we have pursued our interest in lipoprotein lipase (LPL) and intravascular lipolysis, focusing on the specific aims in our original grant application. Our studies have been productive, yielding papers that describe insights into the LPL sequences that interact with GPIHBP1 and insights into the cellular mechanisms for GPIHBP1-mediated transport of LPL across endothelial cells. In this renewal application, we have proposed three new specific aims.
The first aim relates to our discovery that some cases of human hypertriglyceridemia are caused by GPIHBP1 autoantibodies. We now need to better characterize this new disease syndrome and define its frequency.
Our second aim relates to our discovery that GPIHBP1 is present in human plasma and that GPIHBP1 levels can be quantified with an ELISA. We now need to determine if GPIHBP1 levels in the plasma are a useful biomarker of metabolic or vascular disease.
Our third aim deals with persistent and fundamental questions regarding the LPL?GPIHBP1 complex, including the stoichiometry of the complex and how its stability and activity are influenced by physiologic variables. We have accumulated substantial preliminary data to support the feasibility of our proposed studies. With regard to the first specific aim, we have already documented GPIHBP1 autoantibodies in plasma samples from six patients with hypertriglyceridemia. One of the patients became pregnant and, as expected, the autoantibodies crossed the placenta. The newborn infant?s plasma contained GPIHBP1 autoantibodies, resulting in extremely severe (but transient) hypertriglyceridemia. The discovery that GPIHBP1 autoantibodies cause hypertriglyceridemia is a translational discovery with major implications for medical diagnostics and therapeutics. We now need to better characterize GPIHBP1 autoantibodies and determine the frequency of the ?GPIHBP1 autoantibody syndrome.? For the second specific aim, we already developed and characterized monoclonal antibodies against human GPIHBP1 and used two of the antibodies to create an ELISA for human GPIHBP1. Our ELISA accurately quantifies GPIHBP1 in the plasma. We are poised to collaborate with leaders of genetic?epidemiology studies to test whether plasma GPIHBP1 levels are a useful biomarker of vascular or metabolic disease. With regard to the third specific aim, we have made substantial progress in understanding the LPL?GPIHBP1 complex and in developing experimental approaches to study that complex. Our studies suggest that there is only a single binding site for GPIHBP1 on newly secreted LPL (despite the fact that LPL is widely presumed to be a homodimer). Related studies suggest that GPIHBP1 binds only one molecule of LPL. We need to confirm these results with additional experimental platforms, including surface plasmon resonance studies. We also need to determine how LPL?GPIHBP1 interactions are affected by physiologic variables such as active triglyceride lipolysis or inhibitor proteins (e.g., ANGPTL4). These studies will add substantially to our understanding of LPL?GPIHBP1 interactions and the physiology of intravascular lipolysis.
Elevated plasma triglyceride levels are associated with an increased risk for cardiovascular disease, and severe forms of hypertriglyceridemia predispose to acute pancreatitis. In this project, we will pursue our discovery of a new human metabolic disease (hypertriglyceridemia due to GPIHBP1 autoantibodies) and test the possibility that plasma GPIHBP1 levels are a useful biomarker for metabolic or vascular diseases.
| Kristensen, Kristian K; Midtgaard, Søren Roi; Mysling, Simon et al. (2018) A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proc Natl Acad Sci U S A 115:E6020-E6029 |
| Miyashita, Kazuya; Fukamachi, Isamu; Nagao, Manabu et al. (2018) An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum. J Clin Lipidol 12:203-210.e1 |
| He, Cuiwen; Weston, Thomas A; Jung, Rachel S et al. (2018) NanoSIMS Analysis of Intravascular Lipolysis and Lipid Movement across Capillaries and into Cardiomyocytes. Cell Metab 27:1055-1066.e3 |
| Larsson, Mikael; Allan, Christopher M; Heizer, Patrick J et al. (2018) Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure. J Lipid Res 59:706-713 |
| He, Cuiwen; Hu, Xuchen; Weston, Thomas A et al. (2018) Macrophages release plasma membrane-derived particles rich in accessible cholesterol. Proc Natl Acad Sci U S A 115:E8499-E8508 |
| Beigneux, Anne P; Miyashita, Kazuya; Ploug, Michael et al. (2017) Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia. N Engl J Med 376:1647-1658 |
| Hu, Xuchen; Sleeman, Mark W; Miyashita, Kazuya et al. (2017) Monoclonal antibodies that bind to the Ly6 domain of GPIHBP1 abolish the binding of LPL. J Lipid Res 58:208-215 |
| Allan, Christopher M; Larsson, Mikael; Jung, Rachel S et al. (2017) Mobility of ""HSPG-bound"" LPL explains how LPL is able to reach GPIHBP1 on capillaries. J Lipid Res 58:216-225 |
| He, Cuiwen; Hu, Xuchen; Jung, Rachel S et al. (2017) High-resolution imaging and quantification of plasma membrane cholesterol by NanoSIMS. Proc Natl Acad Sci U S A 114:2000-2005 |
| Allan, Christopher M; Tran, Deanna; Tu, Yiping et al. (2017) A hypomorphic Egfr allele does not ameliorate the palmoplantar keratoderma caused by SLURP1 deficiency. Exp Dermatol 26:1134-1136 |
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