Skip to main content
SpringerLink
Log in
Book cover

Stearoyl-CoA Desaturase Genes in Lipid Metabolism pp 73–84Cite as

Stearoyl-CoA Desaturase-1 in the Regulation of Toll-Like Receptor Signaling and Endoplasmic Reticulum Stress Signaling

  • Chapter
  • First Online:

  • 1025 Accesses

Abstract

Stearoyl-CoA desaturases are a family of enzymes that play a crucial role in the endogenous synthesis of monounsaturated fatty acids, also known as de novo lipogenesis. Of the four known SCD isoforms, stearoyl-CoA desaturase 1 (SCD1) is the most predominant and most ubiquitously expressed, with the highest induction in lipogenic tissues such as liver and adipose tissue. In this chapter, we will discuss the effects of SCD1 and its substrates, saturated fatty acids, on three levels as shown in Fig. 7.4. First, we will introduce SCD1 and its role in lipid biosynthesis. Next, we will cover intermediate responses to SCD1 modulation, such as inflammation and ER stress. Finally, we will expand our discussion of SCD1 into the context of vascular diseases such as atherosclerosis and vascular calcification. The studies discussed in this chapter are significant because cardiovascular diseases are some of the leading causes of mortality worldwide. In these diseases, lipids such as fatty acids and their metabolites can accumulate and lead to cellular dysfunction and death, known as lipotoxicity. Since SCD1 plays such an important role in fatty acid formation, a deeper understanding of this pivotal enzyme may significantly contribute to further advances in the treatment of lipid-related diseases.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Anderson EK, Hill AA, Hasty AH (2012) Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arterioscler Thromb Vasc Biol 32:1687–1695

    Article  PubMed  CAS  Google Scholar 

  • Brookheart RT, Michel CI, Schaffer JE (2009) As a matter of fat. Cell Metab 10:9–12

    Article  PubMed  CAS  Google Scholar 

  • Brown JM, Chung S, Sawyer JK, Degirolamo C, Alger HM, Nguyen T, Zhu X, Duong MN, Wibley AL, Shah R, Davis MA, Kelley K, Wilson MD, Kent C, Parks JS, Rudel LL (2008) Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis. Circulation 118:1467–1475

    Article  PubMed  CAS  Google Scholar 

  • Brown JM, Chung S, Sawyer JK, Degirolamo C, Alger HM, Nguyen TM, Zhu X, Duong MN, Brown AL, Lord C, Shah R, Davis MA, Kelley K, Wilson MD, Madenspacher J, Fessler MB, Parks JS, Rudel LL (2010) Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 30:24–30

    Article  PubMed  CAS  Google Scholar 

  • Choi SE, Jung IR, Lee YJ, Lee SJ, Lee JH, Kim Y, Jun HS, Lee KW, Park CB, Kang Y (2011) Stimulation of lipogenesis as well as fatty acid oxidation protects against palmitate-induced INS-1 beta-cell death. Endocrinology 152:816–827

    Article  PubMed  CAS  Google Scholar 

  • Dobrzyn A, Dobrzyn P, Miyazaki M, Sampath H, Chu K, Ntambi JM (2005) Stearoyl-CoA desaturase 1 deficiency increases CTP:choline cytidylyltransferase translocation into the membrane and enhances phosphatidylcholine synthesis in liver. J Biol Chem 280:23356–23362, Epub 2005 Apr 13

    Article  PubMed  CAS  Google Scholar 

  • Duan X, Zhou Y, Teng X, Tang C, Qi Y (2009) Endoplasmic reticulum stress-mediated apoptosis is activated in vascular calcification. Biochem Biophys Res Commun 387:694–699

    Article  PubMed  CAS  Google Scholar 

  • Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow ME, Fazio S, Wiest MM, Watkins SM, Linton MF, Hotamisligil GS (2009) Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med 15:1383–1391

    Article  PubMed  CAS  Google Scholar 

  • Flowers JB, Rabaglia ME, Schueler KL, Flowers MT, Lan H, Keller MP, Ntambi JM, Attie AD (2007) Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes 56:1228–1239

    Article  PubMed  CAS  Google Scholar 

  • Flowers MT, Keller MP, Choi Y, Lan H, Kendziorski C, Ntambi JM, Attie AD (2008) Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet. Physiol Genomics 33:361–372

    Article  PubMed  CAS  Google Scholar 

  • Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528–531

    Article  PubMed  CAS  Google Scholar 

  • Gao J, Ishigaki Y, Yamada T, Kondo K, Yamaguchi S, Imai J, Uno K, Hasegawa Y, Sawada S, Ishihara H, Oyadomari S, Mori M, Oka Y, Katagiri H (2011) Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses. Circulation 124:830–839

    Article  PubMed  Google Scholar 

  • Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5:167–179

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276:16683–16689

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, Hwang DH (2003a) Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44:479–486

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH (2003b) Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 278:37041–37051

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, Lee WH, Fitzgerald KA, Hwang DH (2004) Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 279:16971–16979

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Ntambi JM (2009) Atherosclerosis: keep your macrophages in shape. Nat Med 15:1357–1358

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Miyazaki M, Flowers MT, Sampath H, Zhao M, Chu K, Paton CM, Joo DS, Ntambi JM (2010) Loss of Stearoyl-CoA desaturase-1 attenuates adipocyte inflammation: effects of adipocyte-derived oleate. Arterioscler Thromb Vasc Biol 30:31–38

    Article  PubMed  Google Scholar 

  • Liu X, Strable MS, Ntambi JM (2011) Stearoyl CoA desaturase 1: role in cellular inflammation and stress. Adv Nutr 2:15–22

    Article  PubMed  Google Scholar 

  • Macdonald ML, Bissada N, Vallance BA, Hayden MR (2009a) Absence of stearoyl-CoA desaturase-1 does not promote DSS-induced acute colitis. Biochim Biophys Acta 1791:1166–1172

    Article  PubMed  CAS  Google Scholar 

  • MacDonald ML, van Eck M, Hildebrand RB, Wong BW, Bissada N, Ruddle P, Kontush A, Hussein H, Pouladi MA, Chapman MJ, Fievet C, van Berkel TJ, Staels B, McManus BM, Hayden MR (2009b) Despite antiatherogenic metabolic characteristics, SCD1-deficient mice have increased inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol 29:341–347

    Article  PubMed  CAS  Google Scholar 

  • Masuda M, Ting TC, Levi M, Saunders SJ, Miyazaki-Anzai S, Miyazaki M (2012) Activating transcription factor 4 regulates stearate-induced vascular calcification. J Lipid Res 53:1543–1552

    Article  PubMed  CAS  Google Scholar 

  • Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G, Bochaton-Piallat ML, Mochizuki N, Kitakaze M (2007) Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116:1226–1233

    Article  PubMed  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  PubMed  CAS  Google Scholar 

  • Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM (2007) Stearoyl CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem 282(4):2483–93

    Article  PubMed  CAS  Google Scholar 

  • Scull CM, Tabas I (2011) Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol 31:2792–2797

    Article  PubMed  CAS  Google Scholar 

  • Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45:42–72

    Article  PubMed  CAS  Google Scholar 

  • Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13:184–190

    Article  PubMed  CAS  Google Scholar 

  • Testerink N, van der Sanden MH, Houweling M, Helms JB, Vaandrager AB (2009) Depletion of phosphatidylcholine affects endoplasmic reticulum morphology and protein traffic at the Golgi complex. J Lipid Res 50:2182–2192

    Article  PubMed  CAS  Google Scholar 

  • Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe−/− and Ldlr−/− mice lacking CHOP. Cell Metab 9:474–481

    Article  PubMed  CAS  Google Scholar 

  • Uryu S, Tokuhiro S, Oda T (2003) beta-Amyloid-specific upregulation of stearoyl coenzyme A desaturase-1 in macrophages. Biochem Biophys Res Commun 303:302–305

    Article  PubMed  CAS  Google Scholar 

  • Van der Sanden MH, Houweling M, van Golde LM, Vaandrager AB (2003) Inhibition of phosphatidylcholine synthesis induces expression of the endoplasmic reticulum stress and apoptosis-related protein CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153). Biochem J 369:643–650

    Article  PubMed  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  PubMed  CAS  Google Scholar 

  • Wei Y, Wang D, Topczewski F, Pagliassotti MJ (2006) Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291:E275–281

    Article  PubMed  CAS  Google Scholar 

  • Zheng Y, Eilertsen KJ, Ge L, Zhang L, Sundberg JP, Prouty SM, Stenn KS, Parimoo S (1999) Scd1 is expressed in sebaceous glands and is disrupted in the asebia mouse. Nat Genet 23:268–270

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, 80045, USA

    Tabitha C. Ting & Makoto Miyazaki

Authors
  1. Tabitha C. Ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Miyazaki .

Editor information

Editors and Affiliations

  1. Departments of Biochemistry and Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA

    James M. Ntambi, Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ting, T.C., Miyazaki, M. (2013). Stearoyl-CoA Desaturase-1 in the Regulation of Toll-Like Receptor Signaling and Endoplasmic Reticulum Stress Signaling. In: Ntambi, Ph.D., J. (eds) Stearoyl-CoA Desaturase Genes in Lipid Metabolism. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7969-7_7

Download citation

Publish with us

Policies and ethics

Search

Navigation