The long-term goals of this project are to define the molecular physiology and biochemistry of dietary fat digestion.
The Specific Aims i n this grant are to: 1) Define the contribution of carboxyl ester lipase (CEL) and pancreatic lipase related protein 2 (PLRP2) to the digestion of dietary fat. 2) Define the physiological functions of procolipase. 3) Test the role of enterostatin in the various phenotypes of the procolipase deficient mice.
In Specific Aim 1 we will measure the absorption of a variety of dietary fats in CEL and PLRP2 deficient mice, which are already available. We will monitor growth and fecal fat absorption. We will evaluate the role of CEL in dietary triglyceride digestion in adult and suckling mice and determine if CEL and PLRP2 contribute to the digestion of a minor dietary lipid, galactolipids. These studies will provide important information about dietary fat digestion particularly in newborns and will influence the development of nutritional therapy for chronically ill patients and premature infants.
In Specific Aim 2, we will expand our studies of procolipase deficient mice that were begun in the last grant period. We will determine if procolipase regulates the body weight set point as suggested by our previous studies. Because procolipase deficient newborns have steatorrhea independent of colipase-dependent pancreatic lipase (PTL), we will analyze neonatal pancreas and breast milk for another colipase dependent lipase. Finally, we will begin investigation to determine if alterations in feeding behavior account for the decreased survival in procolipase deficient mice. These studies will define the role of procolipase in dietary fat digestion in suckling animals when PTL is absent and will potentially identify new roles for colipase in weight regulation and in fetal development. The last Specific Aim is designed to rigorously test the hypothesis that enterostatin regulates appetite. Enterostatin is a peptide released from procolipase after it enters the duodenum. When injected into an animal enterostatin decreases fat intake. We have created enterostatin deficient, colipase sufficient mice and will determine the effects of endogenous enterostatin deficiency on weight gain and appetite. These studies will test the hypothesis that enterostatin regulates satiety and will provide an animal model for testing potential pharmaceutical agents that modulate this pathway. Taken together the completion of these studies will increase our understanding of fat digestion and the regulation of fat intake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053100-08
Application #
6983436
Study Section
Metabolism Study Section (MET)
Program Officer
May, Michael K
Project Start
1998-06-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
8
Fiscal Year
2006
Total Cost
$296,371
Indirect Cost
Name
Children's Hosp Pittsburgh/Upmc Health Sys
Department
Type
DUNS #
044304145
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
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