? The objective of this proposal is to investigate the molecular mechanisms of dietary lipid absorption and the role of fatty acid tranport protein 4 (FATP4), hypothesized to be the dominant small intestine long-chain fatty acid transporter. Because FATP4 null mice die shortly after birth, the role of FATP4 in dietary lipid absorption has not been assessed. Using a transgene expressed exclusively in skin, FATP4 null mice have been rescued and express no FATP4 in the intestine. These mice consume 10% more food per gram body weight than controls, yet manifest reduced serum triglycerides and cholesterol, differences that become more pronounced after consumption of a high-fat diet. These results suggest defective lipid absorption in rescued mutants, which may be partially compensated.
The specific aims of this project are to determine the role of FATP4 in dietary fatty acid absorption, cholesterol homeostasis, and lipid processing through in vivo absorption, metabolic, and packaging studies. The necessity of the acyl-CoA synthetase activity of FATP4 in vivo will be investigated using a transgene with an inactive acyl-CoA synthetase domain bred onto the FATP4 null mouse. Finally, oligomerization of FATP4 will be investigated through immunoprecipitation and examination of dominant-negative activity of a mutated FATP4. These studies will advance our understanding of how dietary lipids are absorbed from the intestines and how FATP4 functions in this regard. ? These studies will be conducted at Washington University and will provide the training and necessary skills for the investigator to make the transition to independent research under the supervision of Nicholas Davidson, with additional scientific and career advice provided from an advisory committee. ? Results from this research will help to understand the mechanisms by which dietary lipids are absorbed from the intestine and may help to understand obesity. Obesity is currently the second leading cause of preventable disease and death in the United States behind cigarette smoking. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK075811-01
Application #
7133948
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2006-07-15
Project End
2009-06-30
Budget Start
2006-07-15
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$85,152
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Shim, Jien; Moulson, Casey L; Newberry, Elizabeth P et al. (2009) Fatty acid transport protein 4 is dispensable for intestinal lipid absorption in mice. J Lipid Res 50:491-500
Moulson, Casey L; Lin, Meei-Hua; White, J Michael et al. (2007) Keratinocyte-specific expression of fatty acid transport protein 4 rescues the wrinkle-free phenotype in Slc27a4/Fatp4 mutant mice. J Biol Chem 282:15912-20