Triglyceride lipases are ubiquitous enzymes required for the digestion of dietary fats, the uptake of fats into tissues and the mobilization of fats insde cells. Consequently, the action of lipases impacts energy and nutrient intake, cardiovascular disease, and abnormal storage of fat in obesity or in hepatosteatosis. Nowhere are lipases more important than in dietary fat digestion. Our long-term goal is to elucidate the physiology and molecular mechanisms of dietary fat digestion by pancreatic lipases. In this application, our objective is to define the molecular properties of colipase and pancreatic lipase related protein 2 (PLRP2) that make them critical for neonatal fat digestion. Our central hypothesis is that colipase and PLRP2 interact with fat globules to efficiently digest specific lipids in human mother's milk. To address our hypothesis we propose to: 1) Determine the molecular details of the interactions of colipase with PTL, PLRP2 and lipids;2) Characterize PLRP2 substrates in mother's milk and 3) Determine if human newborns require PLRP2 for efficient fat digestion and weight gain. The outcome of our work will define the interactions between the colipase-PLRP2 complex and dietary lipids, the substrate specificity of PLRP2 and the impact of a loss-of-function mutation in PLIPRP2 on fat absorption in newborns. The results will advance knowledge of dietary fat digestion by pancreatic lipases. Importantly, completion of the Aims will facilitate the bench-to-bedside development of novel nutritional therapies such as more effective formulas or enzyme replacement that will transform care and improve outcome of premature infants and critically ill newborns and

Public Health Relevance

Triglyceride lipases are ubiquitous enzymes required for the digestion of dietary fats, the uptake of fats into tissues and the mobilization of fats inside cell. Lipases figure prominently in nutritional therapy for newborns who consume more fat per kg body weight than at any time of life. Consequently, a thorough understanding of the lipases that digest dietary fats in newborns is required to develop novel nutritional therapies such as more effective formulas or enzyme replacement that will improve care and outcome of premature infants and critically ill newborns.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK080820-05A1
Application #
8692178
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Johnson, Karin; Ross, Leah; Miller, Rita et al. (2013) Pancreatic lipase-related protein 2 digests fats in human milk and formula in concert with gastric lipase and carboxyl ester lipase. Pediatr Res 74:127-32
Xiao, Xunjun; Ferguson, Michael R; Magee, Kelsey E et al. (2013) The Arg92Cys colipase polymorphism impairs function and secretion by increasing protein misfolding. J Lipid Res 54:514-21
Xiao, Xunjun; Ross, Leah E; Sevilla, Wednesday A et al. (2013) Porcine pancreatic lipase related protein 2 has high triglyceride lipase activity in the absence of colipase. Biochim Biophys Acta 1831:1435-41
Ross, Leah E; Xiao, Xunjun; Lowe, Mark E (2013) Identification of amino acids in human colipase that mediate adsorption to lipid emulsions and mixed micelles. Biochim Biophys Acta 1831:1052-9
Xiao, Xunjun; Mukherjee, Amitava; Ross, Leah E et al. (2011) Pancreatic lipase-related protein-2 (PLRP2) can contribute to dietary fat digestion in human newborns. J Biol Chem 286:26353-63
Xiao, Xunjun; Ross, Leah E; Miller, Rita A et al. (2011) Kinetic properties of mouse pancreatic lipase-related protein-2 suggest the mouse may not model human fat digestion. J Lipid Res 52:982-90