Hyperlipidemia is a major public health problem. The objective of this proposal is to define the role of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in plasma triglyceride metabolism. During the past few months, we have made a stunning observation-that GPIHBP1 plays a major role in the metabolism of triglyceride-rich lipoproteins in the plasma. Remarkably, the sole phenotype of male and female Gpihbpl-deficient mice on a chow diet is chylomicronemia, with plasma triglycerides of -10,000 mg/ dl. GPIHBP1 is expressed on the surface of cells, mainly in adipose tissue and heart, the principal tissue sites of lipolysis of triglyceride-rich lipoproteins. Because the expression pattern of GPIHBP1 faithfully mirrors that of lipoprotein lipase (LPL), it is overwhelmingly likely that the hypertriglyceridemia in Gpihbpl - deficient mice is due to impaired lipolysis of chylomicrons and very low density lipoproteins (VLDL). Only one description of GPIHBP1 exists in the literature. That study that showed that GPIHBP1 can bind to high density lipoproteins in cultured cells. However, no link was made to triglyceride-rich lipoproteins, and the in vivo physiologic importance of the molecule was not explored. We propose that GPIHBP1 plays a major role in the lipolysis of triglyceride-rich lipoproteins. We hypothesize that GPIHBP1 is involved in """"""""capturing"""""""" lipoproteins as they flow through capillaries and recruiting LPL (from a reservoir on the surface of cells) so that lipolysis can begin. However, at this stage, there are more questions than answers about the functions of GPIHBPL in Specific Aim 1 of this proposal; we will further characterize the hyperlipidemia in Gpihbpl-deficient mice and to test the hypothesis that the severe chylomicronemia is related to defective LPL-mediated lipolysis along the capillary endothelium.
In Specific Aim 2, we will define the pattern of Gpihbpl expression in various mouse tissues and determine if Gpihbpl expression is regulated according to different metabolic states (e.g., fasting, refeeding). Defining the Gpihbpl expression will be facilitated by the fact that the Gpihbpl knockout mice have a lacZ reporter.
In Specific Aim 3, we will test the idea that GPIHBP1 binds directly to triglyceride-rich lipoproteins and/or to LPL, thereby facilitating lipolysis. ? ? ?
| 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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