Role of Stearoyl-CoA Desaturase in Metabolism

Summary

Principal Investigator: James Ntambi
Affiliation: University of Wisconsin
Country: USA
Abstract: 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.
Funding Period: 2002-08-01 - 2006-06-30
more information: NIH RePORT

Top Publications

  1. pmc Ferrous, but not ferric, iron maintains homeostasis in Histoplasma capsulatum triacylglycerides
    Robert Zarnowski
    Department of Medical Microbiology and Immunology, University of Wisconsin, 416 Service Memorial Institute, 1300 University Avenue, Madison, WI 53705, USA
    Curr Microbiol 57:153-7. 2008
  2. ncbi Stearoyl-CoA desaturase 1 deficiency increases insulin signaling and glycogen accumulation in brown adipose tissue
    Shaikh Mizanoor Rahman
    Dept of Biochemistry, University of Wisconsin, 433 Babcock Drive, Madison, WI 53706, USA
    Am J Physiol Endocrinol Metab 288:E381-7. 2005
  3. ncbi Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis
    Makoto Miyazaki
    Department of Biochemistry, University of Wisconsin Madison, 433 Babcock Drive, Madison, WI 53706, USA
    Cell Metab 6:484-96. 2007
  4. pmc Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia
    Rebecca Mar-Heyming
    Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Arterioscler Thromb Vasc Biol 28:1193-9. 2008
  5. doi Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism
    Matthew T Flowers
    Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA
    Curr Opin Lipidol 19:248-56. 2008
  6. pmc Biochemical and physiological function of stearoyl-CoA desaturase
    Chad M Paton
    Department of Biochemistry, University of Wisconsin, 433 Babcock Dr, Madison, WI 53706, USA
    Am J Physiol Endocrinol Metab 297:E28-37. 2009
  7. pmc Stearoyl-CoA desaturase and its relation to high-carbohydrate diets and obesity
    Matthew T Flowers
    Department of Biochemistry, University of Wisconsin, 433 Babcock Drive, Madison, Wisconsin 53706, USA
    Biochim Biophys Acta 1791:85-91. 2009
  8. pmc Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice
    Makoto Miyazaki
    Department of Biochemistry, University of Wisconsin Madison, 433, Babcock Drive, Madison, WI 53706, USA
    Biochem Biophys Res Commun 380:818-22. 2009
  9. pmc Skin-specific deletion of stearoyl-CoA desaturase-1 alters skin lipid composition and protects mice from high fat diet-induced obesity
    Harini Sampath
    Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA
    J Biol Chem 284:19961-73. 2009
  10. pmc Neutral storage lipids of Histoplasma capsulatum: effect of culture age
    Robert Zarnowski
    Department of Medical Microbiology and Immunology, University of Wisconsin, 416 Service Memorial Institute, 1300 University Avenue, Madison, WI 53706, USA
    Curr Microbiol 56:110-4. 2008

Scientific Experts

  • Robert Zarnowski
  • James Ntambi
  • Makoto Miyazaki
  • Matthew T Flowers
  • Agnieszka Dobrzyn
  • Kiki Chu
  • Chad M Paton
  • Harini Sampath
  • Weng Chi Man
  • Sudha B Biddinger
  • Pawel Dobrzyn
  • Xueqing Liu
  • Minghui Zhao
  • Rebecca Mar-Heyming
  • C Ronald Kahn
  • Seong Ho Lee
  • Shaikh Mizanoor Rahman
  • Diane Seohee Joo
  • Ruth Sullivan
  • Daphna Weissglas-Volkov
  • Christopher Plaisier
  • Aldons J Lusis
  • Nicholas A Kolaitis
  • Rita M Cantor
  • Narimaan Sadaat
  • Tjerk W A de Bruin
  • Paivi Pajukanta
  • Jeremie Boucher
  • Jeffrey M Friedman
  • Katrine Almind
  • Paul Cohen
  • D Grahame Hardie
  • Esra Asilmaz
  • Efi Kokkotou

Detail Information

Publications20

  1. pmc Ferrous, but not ferric, iron maintains homeostasis in Histoplasma capsulatum triacylglycerides
    Robert Zarnowski
    Department of Medical Microbiology and Immunology, University of Wisconsin, 416 Service Memorial Institute, 1300 University Avenue, Madison, WI 53705, USA
    Curr Microbiol 57:153-7. 2008
    ..capsulatum to acquire iron in its reduced, more soluble, ferrous form, and therefore, the availability of iron may be the underlying reason for the observed iron-maintained homeostasis in H. capsulatum triacylglycerols...
  2. ncbi Stearoyl-CoA desaturase 1 deficiency increases insulin signaling and glycogen accumulation in brown adipose tissue
    Shaikh Mizanoor Rahman
    Dept of Biochemistry, University of Wisconsin, 433 Babcock Drive, Madison, WI 53706, USA
    Am J Physiol Endocrinol Metab 288:E381-7. 2005
    ..Taken together, these studies illustrate increased insulin signaling and increased glycogen metabolism in BAT of SCD1(-/-) mice...
  3. ncbi Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis
    Makoto Miyazaki
    Department of Biochemistry, University of Wisconsin Madison, 433 Babcock Drive, Madison, WI 53706, USA
    Cell Metab 6:484-96. 2007
    ....
  4. pmc Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia
    Rebecca Mar-Heyming
    Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Arterioscler Thromb Vasc Biol 28:1193-9. 2008
    ..We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL)...
  5. doi Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism
    Matthew T Flowers
    Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706, USA
    Curr Opin Lipidol 19:248-56. 2008
    ..This review evaluates the latest advances in our understanding of the pivotal role of stearoyl-coenzyme A desaturase 1 in health and disease...
  6. pmc Biochemical and physiological function of stearoyl-CoA desaturase
    Chad M Paton
    Department of Biochemistry, University of Wisconsin, 433 Babcock Dr, Madison, WI 53706, USA
    Am J Physiol Endocrinol Metab 297:E28-37. 2009
    ..In this article, we summarize the recent and timely advances concerning the important role of SCD in the biochemistry and physiology of lipid metabolism...
  7. pmc Stearoyl-CoA desaturase and its relation to high-carbohydrate diets and obesity
    Matthew T Flowers
    Department of Biochemistry, University of Wisconsin, 433 Babcock Drive, Madison, Wisconsin 53706, USA
    Biochim Biophys Acta 1791:85-91. 2009
    ..In this review, we address the association of high-carbohydrate diets with increased SCD activity and summarize the current literature on the subject of SCD1 and body weight regulation...
  8. pmc Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice
    Makoto Miyazaki
    Department of Biochemistry, University of Wisconsin Madison, 433, Babcock Drive, Madison, WI 53706, USA
    Biochem Biophys Res Commun 380:818-22. 2009
    ..These data uncouple the effects of SCD1 deficiency on weight loss from those on insulin sensitivity and suggest a beneficial effect of SCD1 inhibition on insulin sensitivity in obese mice that express a functional leptin gene...
  9. pmc Skin-specific deletion of stearoyl-CoA desaturase-1 alters skin lipid composition and protects mice from high fat diet-induced obesity
    Harini Sampath
    Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA
    J Biol Chem 284:19961-73. 2009
    ..This results in up-regulation of thermogenic processes for temperature maintenance at the expense of fuel economy, illustrating cross-talk between the skin and peripheral tissues in maintaining energy homeostasis...
  10. pmc Neutral storage lipids of Histoplasma capsulatum: effect of culture age
    Robert Zarnowski
    Department of Medical Microbiology and Immunology, University of Wisconsin, 416 Service Memorial Institute, 1300 University Avenue, Madison, WI 53706, USA
    Curr Microbiol 56:110-4. 2008
    ..capsulatum, but also will contribute to better understanding of biology and pathogenesis of this fungus and, consequently, can help in the discovery of more effective antifungal drugs...
  11. pmc Typing of Histoplasma capsulatum strains by fatty acid profile analysis
    Robert Zarnowski
    Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA
    J Med Microbiol 56:788-97. 2007
    ..brasiliensis and S. schenckii were shifted away. These data suggest that fatty acid profiling can be used in H. capsulatum strain classification and epidemiological studies that require strain differentiation at the intraspecies level...
  12. ncbi Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle
    Agnieszka Dobrzyn
    Dept of Biochemistry, Univ of Wisconsin, 433 Babcock Dr, Madison, WI 53706, USA
    Am J Physiol Endocrinol Metab 288:E599-607. 2005
    ..Taken together, these results indicate that SCD1 deficiency reduces ceramide synthesis by decreasing SPT expression and increasing the rate of beta-oxidation in oxidative muscles...
  13. ncbi Stearoyl-CoA desaturase 1 deficiency increases CTP:choline cytidylyltransferase translocation into the membrane and enhances phosphatidylcholine synthesis in liver
    Agnieszka Dobrzyn
    Department of Biochemistry, University of Wisconsin Madison, 53706, USA
    J Biol Chem 280:23356-62. 2005
    ..Our study revealed that SCD1 deficiency specifically increases CCT activity by promoting its translocation into membrane and enhances PC biosynthesis in liver...
  14. ncbi Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
    Diabetes 54:1314-23. 2005
    ..Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome...
  15. ncbi Polyunsaturated fatty acids do not activate AMP-activated protein kinase in mouse tissues
    Agnieszka Dobrzyn
    Department of Biochemistry, University of Wisconsin Madison, Madison, WI 53706, USA
    Biochem Biophys Res Commun 332:892-6. 2005
    ..The data suggest that PUFA are not involved in AMPK activation in mouse tissues and that the increased activity of AMPK in SCD1-/- mice is probably PUFA-independent...
  16. ncbi Membrane topology of mouse stearoyl-CoA desaturase 1
    Weng Chi Man
    Biochemistry andNutritional Sciences, University of Wisconsin Madison, 53706, USA
    J Biol Chem 281:1251-60. 2006
    ....
  17. ncbi Identification of mouse palmitoyl-coenzyme A Delta9-desaturase
    Makoto Miyazaki
    Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA
    J Lipid Res 47:700-4. 2006
    ..We identify SCD3 as a mammalian palmitotyl-CoA Delta9-desaturase, and its existence in mouse helps explain distinct physiological roles for each SCD isoform...
  18. ncbi Colocalization of SCD1 and DGAT2: implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis
    Weng Chi Man
    Department of Biochemistry, University of Wisconsin Madison, Madison, WI 53706, USA
    J Lipid Res 47:1928-39. 2006
    ..By performing subcellular fractionation using mouse livers, we also show, for the first time, that SCD is present in the mitochondria-associated membrane...
  19. ncbi Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, One Joslin Pl, Boston, MA 02215, USA
    Diabetes 55:2032-41. 2006
    ..Thus, the effect of leptin on SCD1 in liver is independent of insulin and SREBP-1c, and leptin, rather than insulin, is the major regulator of hepatic MUFA synthesis in obesity-linked diabetes...
  20. pmc Loss of Stearoyl-CoA desaturase-1 attenuates adipocyte inflammation: effects of adipocyte-derived oleate
    Xueqing Liu
    Department of Biochemistry, University of Wisconsin, Madison, 433 Babcock Dr, Madison, WI 53706, USA
    Arterioscler Thromb Vasc Biol 30:31-8. 2010
    ..This study aimed at identify the effects of stearoyl-CoA desaturase-1 (SCD1) on the inflammatory response of a paracrine network involving adipocytes, macrophages, and endothelial cells...