Molecular Mechanisms of Dietary Fat Digestion by Pancreatic Lipases

描述(申请人提供)：甘油三酯脂肪酶是一种普遍存在的酶，需要消化饮食脂肪，脂肪吸收到组织和动员脂肪进入细胞。因此，脂肪酶的作用影响能量和营养的摄入，心血管疾病，以及肥胖或肝骨病中脂肪的异常储存。脂肪酶在饮食脂肪消化中最重要。我们的长期目标是阐明胰腺脂肪酶消化膳食脂肪的生理和分子机制。在这个应用中，我们的目标是确定脂肪酶和胰腺脂肪酶相关蛋白2的分子性质。 (PLRP2)，使它们对新生儿脂肪消化至关重要。我们的中心假设是，Colipase和PLRP2与脂肪球相互作用，有效地消化母乳中的特定脂肪。为了解释我们的假设，我们建议：1)确定磷脂酶与PTL、PLRP2和脂质相互作用的分子细节；2)确定母乳中PLRP2底物的特征；3)确定人类新生儿是否需要PLRP2来有效消化脂肪和增加体重。我们的工作结果将确定Colipase-PLRP2复合体与饮食脂质之间的相互作用，PLRP2的底物特异性，以及PLIPRP2功能缺失突变对新生儿脂肪吸收的影响。这一结果将促进人们对胰腺脂肪酶消化膳食脂肪的认识。重要的是，完成这些目标将促进新的营养疗法的开发，例如更有效的配方或酶替代，将改变护理并改善早产儿和危重新生儿的结局。

DESCRIPTION (provided by applicant): 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