Our Program Project Grant (PPG), New Molecules in Triglyceride Metabolism and Adipogenesis, is guided by a unifying theme-to understand mechanisms for triglyceride delivery to peripheral tissues, triglyceride synthesis, and adipogenesis. The topic of this PPG is highly relevant to obesity and hyperlipidemia, two public health problems that are central to the mission of the NHLBI. Working as a team over the past 5 years, the Project and Core Leaders of this PPG have studied new molecules with crucial roles in triglyceride delivery to cells, triglyceride synthesis within cells, and adipogenesis. These studies identified new regulators of lipid metabolism and adipogenesis and have uncovered new causes of human disease. For the next 5 years, our PPG team will be guided by the same objective-to understand the mechanisms underlying obesity and metabolic disease. This PPG is organized into three Component Projects and two Cores. Project 1, Function of GPIHBP1 in Triglyceride Metabolism, will be led by Dr. Stephen G. Young. This project focuses on a novel endothelial cell protein, GPIHBP1, and its role in plasma triglyceride metabolism and the delivery of lipid nutrients to adipose tissue, heart, and skeletal muscle. Project 2, Lipin Protein Family Interactions, Lipid Intermediates, and Disease, will be led by Dr Karen Reue. Dr. Reue's discovery of the lipin family of enzymes set the stage for new studies on the regulation of triglyceride synthesis and the control of adipogenesis. Project 3, Novel Pathways for Triglyceride Storage and Adipogenesis, will be led by Dr. Peter Tontonoz. Dr. Tontonoz identified new molecules controlling lipid metabolism and adipogenesis, including TLE3 and IDOL (inducible degrader of the LDL receptor). Dr. Tontonoz will decipher mechanisms by which these new players in lipid metabolism affect adipogenesis. A Mouse Model and Protein Expression Core (Core A) will create new lines of genetically modified mice and will produce purified proteins for biochemical studies and antibody production. An Administrative Core (Core B) will facilitate the efforts by all three Component Projects, organize advisory board meetings, and ensure compliance with institutional and NIH guidelines.
Our country faces an epidemic of hyperlipidemia, metabolic disease, and obesity-exacting a horrific toll on patients, families, and our nation's health care budget. The guiding objective for this PPG is to understand the molecular mechanisms that govern fuel delivery to cells, hyperlipidemia, triglyceride synthesis, and adipogenesis. Pursuing this objective should lead to new treatments for metabolic disease and obesity.
|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|
|Gao, Jie; Marosi, Mate; Choi, Jinkuk et al. (2017) The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. Elife 6:|
|Allan, Christopher M; Jung, Cris J; Larsson, Mikael et al. (2017) Mutating a conserved cysteine in GPIHBP1 reduces amounts of GPIHBP1 in capillaries and abolishes LPL binding. J Lipid Res 58:1453-1461|
|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|
|Hu, Xuchen; Dallinga-Thie, Geesje M; Hovingh, G Kees et al. (2017) GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia. J Clin Lipidol 11:964-971|
|Zhang, Li; Rajbhandari, Prashant; Priest, Christina et al. (2017) Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP. Elife 6:|
|He, Cuiwen; Hu, Xuchen; Jung, Rachel S et al. (2017) Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1. JCI Insight 2:|
|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|
|Wang, Jiexin; Rajbhandari, Prashant; Damianov, Andrey et al. (2017) RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs. J Clin Invest 127:987-1004|
|Wang, Huan; Airola, Michael V; Reue, Karen (2017) How lipid droplets ""TAG"" along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta 1862:1131-1145|
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