Stearoyl-CoA desaturase is a central lipogenic enzyme catalyzing all reactions in the synthesis of monounsaturated fatty acids mainly oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides, wax esters and cholesterol esters. Several SCD gene isoforms (SCD1, SCD2, SCD3) exist in the mouse. We have found that mice with a targeted disruption of the SCD1 isoform (SCD1-/-) have reduced body fat, plasma leptin and insulin levels and a reduced rate of triglyceride synthesis in liver. Compared to wild type mice, SCD1-/- mice are lean and resistant to high fat diet-induced obesity. The expression of lipogenic genes is reduced in the SCD1-/- mice. It is well known that fatty acid and triglyceride synthesis is regulated by the insulin-dependent gene expression and maturation of the sterol regulatory element binding protein-ic (SREBP-1c). What we found instead is that while the SREBP-1c gene expression was not altered in the SCD1-/- mice, the maturation of the SREBP-1 protein into its transcriptionally active form is blocked. The levels of ketone bodies and the mRNA levels of the peroxisome proliferator activated receptor alpha (PPAR-alpha) target genes are increased suggesting increased fatty acid Beta-oxidation in the SCD1-/- mice. We hypothesize that SCD1 deficiency induces a signal that down regulates lipogenesis by modulating the SREBP-1 protein maturation and activates the PPARa pathway to partition fatty acids towards fatty acid Beta-oxidation. We shall design experiments to address this hypothesis using wild type (SCD1 +/+), heterozygotes (SCD1+/-) and homozygotes (SCD1-/-) mice as well as primary hepatocytes derived from these animals.
The specific aims of this proposal are: 1. To determine whether SCD1 deficiency causes a blockage in the processing of the liver SREBP-1 protein to its mature form and down-regulates lipogenesis. 2. To elucidate how SCD1 deficiency up-regulates fatty acid Beta-oxidation. Overall, our studies wil provide physiologically relevant information on the role of stearoyl-CoA desaturase gene expression in lipid and carbohydrate metabolism and will enhance our understanding of metabolic control of lipogenesis and dysregulation in diabetes and obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062388-01
Application #
6535650
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Tondravi, Mehrdad M
Project Start
2002-08-01
Project End
2006-06-30
Budget Start
2002-08-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$311,090
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Dumas, Sabrina; Ntambi, James M (2017) Co-conspirators in a new mechanism for the degradation of ?9-desaturase. J Biol Chem 292:19987-19988
ALJohani, Ahmed M; Syed, Deeba N; Ntambi, James M (2017) Insights into Stearoyl-CoA Desaturase-1 Regulation of Systemic Metabolism. Trends Endocrinol Metab 28:831-842
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Rogowski, Michael P; Flowers, Matthew T; Stamatikos, Alexis D et al. (2013) SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPAR? expression in mice. J Lipid Res 54:2636-46
Flowers, Matthew T; Ade, Lacmbouh; Strable, Maggie S et al. (2012) Combined deletion of SCD1 from adipose tissue and liver does not protect mice from obesity. J Lipid Res 53:1646-53

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