The objectives of this proposal are to identify the structural features of lipoprotein lipase (LPL) required for binding to GPIHBP1 and to define mechanisms by which LPL is transported across endothelial cells. We discovered that GPIHBP1, an endothelial cell protein, binds LPL and is absolutely required for the lipolytic processing of triglyceride-rich lipoproteins. We showed that an absence of GPIHBP1 in mice causes severe hypertriglyceridemia (chylomicronemia) and that humans with GPIHBP1 mutations exhibit the same phenotype. Initially, we proposed that GPIHBP1 was a binding site for LPL in capillaries, but we recently found that GPIHBP1 has a second role-transporting LPL from the extracellular spaces into the capillary lumen. The identification of GPIHBP1 as the LPL transporter solved a longstanding mystery of plasma lipid metabolism, posing many new questions for investigation. Among these are: What amino acid sequences within LPL are important for binding to GPIHBP1? Do certain LPL mutations cause disease by abolishing LPL's ability to bind to GPIHBP1? Do other mutations enhance LPL transport? What is the efficiency of LPL transport across endothelial cells? Is LPL movement across capillaries bidirectional? Is LPL transported across capillaries in transcytotic vesicles? We have begun to investigate each of these issues. We have identified amino acid substitutions within the carboxyl terminus of LPL that abolish its ability to bind to GPIHBP1. These mutations have provided important clues regarding the location of LPL's GPIHBP1-binding domain, but many more studies are required to fully understand LPL-GPIHBP1 interactions. We have made great progress in understanding mechanisms of LPL transport, both in vitro and in vivo. Our studies have taken advantage of a host of new antibody reagents and expertise with both confocal and electron microscopy. We have two specific aims, each designed to better understand lipolysis in health and disease.
In Aim 1, we will test the hypothesis that the carboxyl terminus of LPL is crucial for binding GPIHBP1 and examine LPL mutations that interfere with GPIHBP1 binding and transport across endothelial cells.
In Aim 2, we will test the hypothesis that LPL is transported across endothelial cells by caveolar-mediated transcytosis. We are excited by these aims, and are poised-with all of the necessary expertise, reagents, and experimental techniques-to carry out the proposed studies.

Public Health Relevance

LPL has a major influence on plasma lipid levels and on the delivery of lipid nutrients to vital tissues. Our goals are to understand LPL mutations that cause hypertriglyceridemia and to understand mechanisms for LPL transport into capillaries (so that lipolysis can proceed). Our topic is highly relevant to human fuel metabolism and to the pathogenesis of hyperlipidemias in humans.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Mysling, Simon; Kristensen, Kristian Kølby; Larsson, Mikael et al. (2016) The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain. Elife 5:e12095
Allan, Christopher M; Larsson, Mikael; Hu, Xuchen et al. (2016) An LPL-specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1. J Lipid Res 57:1889-1898
Fong, Loren G; Young, Stephen G; Beigneux, Anne P et al. (2016) GPIHBP1 and Plasma Triglyceride Metabolism. Trends Endocrinol Metab 27:455-69
Dijk, Wieneke; Beigneux, Anne P; Larsson, Mikael et al. (2016) Angiopoietin-like 4 promotes intracellular degradation of lipoprotein lipase in adipocytes. J Lipid Res 57:1670-83
Mysling, Simon; Kristensen, Kristian Kølby; Larsson, Mikael et al. (2016) The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding. Elife 5:
Adeyo, O; Oberer, M; Ploug, M et al. (2015) Heterogeneity in the properties of mutant secreted lymphocyte antigen 6/urokinase receptor-related protein 1 (SLURP1) in Mal de Meleda. Br J Dermatol 173:1066-9
Brown, W Virgil; Goldberg, Ira J; Young, Stephen G (2015) JCL Roundtable: Hypertriglyceridemia due to defects in lipoprotein lipase function. J Clin Lipidol 9:274-80
Beigneux, Anne P; Fong, Loren G; Bensadoun, André et al. (2015) GPIHBP1 missense mutations often cause multimerization of GPIHBP1 and thereby prevent lipoprotein lipase binding. Circ Res 116:624-32
Bensadoun, André; Mottler, Charlene D; Pelletier, Chris et al. (2014) A new monoclonal antibody, 4-1a, that binds to the amino terminus of human lipoprotein lipase. Biochim Biophys Acta 1841:970-6
Goulbourne, Chris N; Gin, Peter; Tatar, Angelica et al. (2014) The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries. Cell Metab 19:849-60

Showing the most recent 10 out of 55 publications