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.
|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|
|Allan, Christopher M; Heizer, Patrick J; Jung, Cris J et al. (2018) Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice. J Dermatol Sci 89:85-87|
|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|
|Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315|
|Rajbhandari, Prashant; Thomas, Brandon J; Feng, An-Chieh et al. (2018) IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure. Cell 172:218-233.e17|
|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|
|Wang, Huan; Airola, Michael V; Reue, Karen (2017) How lipid droplets ""TAG"" along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1131-1145|
|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:|
|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|
Showing the most recent 10 out of 143 publications