Non-alcoholic steatosis is highly associated with the development and complications of adult onset-diabetes. Dietary (n-6) and (n-3) polyunsaturated fatty acids (PUFA) reduce the risk of developing steatosis because they function to shift the balance of hepatic fatty acid metabolism away from triglyceride synthesis and toward fatty acid oxidation. PUFA elicit their effects by coordinately suppressing the expression of lipogenic genes (e.g. fatty acid synthase, FAS) while concomitantly inducing the expression of oxidative genes. PUFA suppress FAS gene transcription by interfering with the DNA binding and transactivation activity of a collection of transcription factors that interact with two separate types of PUFA response regions (PUFA-RR). The -118/-43 PUFA-RRFAS involves SREBP-1, NF-Y and Sp1 binding and in this sense has similarities to the PUFA-RR of the S14 gene. The -7350/-7000 PUFA-RRFAS contains a carbohydrate response element and a DR-1 that binds HNF-4 and PPARg and in this sense is similar to the PUFA-RR of the pyruvate kinase gene. PUFA govern the -118/-43 site by reducing the nuclear abundance of SREBP-1c and possibly by inhibiting the DNA binding activity of NF-Y and Sp1. PUFA lower the nuclear levels of SREBP-1 because PUFA inhibit the proteolytic release of mature SREBP-1, and because they accelerate SREBP-1 mRNA decay which in turn reduces the size of the SREBP-1 precursor pool. PUFA regulation of the factors in the - 7350/-7000 PUFA-RR is unknown, but may involve HNF-4 and a unique CHO-RF.
The AIMS of this renewal application are to: (a) employ in vivo footprinting and chromatin immuno-precipitation (CHIP) assays to demonstrate that PUFA decrease the in vivo binding of NF-Y and Sp1 to the -118/-43 PUFA-RRFAS; (b) utilize in vivo footprinting to identify cis-elements in the -7350/-7000 PUFA-RRFAS targeted by PUFA, and apply the CHIP assay to determine if PUFA reduce HNF-4 binding to the -7105/-7094 DR-1 in this distal PUFA-RR; (c) determine if PUFA reduce the DNA binding activity of NF-Y, Sp1, and HNF-4 by enhancing their phosphorylation state through a mechanism that involves interference with the glucose activation of phosphatase 2A, or through activation of AMP-kinase; and (d) identify the PUFA-instability element within the SREBP-1 mRNA responsible for accelerated SREBP-1 mRNA decay. The proposed research continues our efforts to identify molecular targets that can be manipulated by diet or drugs for the purpose of reducing cellular lipid accumulation and hence lessen a complication of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053872-08
Application #
6926995
Study Section
Metabolism Study Section (MET)
Program Officer
May, Michael K
Project Start
1999-02-15
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
8
Fiscal Year
2005
Total Cost
$276,544
Indirect Cost
Name
Lsu Pennington Biomedical Research Center
Department
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
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