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Stearoyl-CoA Desaturase Genes in Lipid Metabolism pp 61–71Cite as

Function and Regulation of Macrophage Stearoyl-CoA Desaturase in Metabolic Disorders

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Abstract

Macrophages are key members of the innate immune system. More recently, a preponderance of evidence suggest that macrophages play an important role in metabolic homeostasis. They are implicated in the pathogenesis of metabolic disorders such as type-2 diabetes and atherosclerosis. Human macrophages express SCD1, while rodent ones express both SCD1 and SCD2. Only a few studies have investigated the regulation of SCD1 expression in macrophages and reported that nuclear transcription factors regulate its expression. Of these, liver X receptor and retinoid X receptor increase SCD1 expression, while CCAAT-/enhancer-binding protein beta, farnesoid-X-receptor, and peroxisome proliferator-activated receptor gamma suppress it. Similar to its regulation in other tissues, stearoyl-CoA desaturase (SCD) expression in macrophages is repressed by polyunsaturated fatty acids (PUFA), especially omega-3 PUFA, via nuclear receptors.

Lipid-laden macrophages, known as macrophage-derived foam cells, characterize the atherosclerotic lesion. Cholesterol efflux from these foam cells, especially via ATP-binding cassette transporter A1 (ABCA1), provides protection against the cholesterol accumulation in foam cells and further progression of the atherosclerotic plaque. Increased expression of SCD destabilizes ABCA1 and reduces cholesterol efflux in macrophages. Omega-3 PUFA can increase cholesterol efflux from foam cells through inhibition of SCD1. However, SCD inhibition in saturated fat-fed animals promotes, rather than suppresses, atherosclerosis in mouse models with hypercholesterolemia. This is attributed to the proinflammatory environment induced by saturated fatty acid-mediated toll-like receptor 4 activation in these models. Fish oil can ameliorate inflammatory responses and the atherosclerotic lesion development caused by SCD1 inhibition. Overall, the exact roles and mechanisms of SCD in modulating macrophage cholesterol efflux and atherosclerosis merit further investigation.

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References

  • Baker PW, Rye KA, Gamble JR, Vadas MA, Barter PJ (1999) Ability of reconstituted high density lipoproteins to inhibit cytokine-induced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. J Lipid Res 40:345–353

    PubMed  CAS  Google Scholar 

  • Baranova I, Vishnyakova T, Bocharov A, Chen Z, Remaley AT, Stonik J, Eggerman TL, Patterson AP (2002) Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect Immun 70:2995–3003

    Article  PubMed  CAS  Google Scholar 

  • Beyea MM, Heslop CL, Sawyez CG, Edwards JY, Markle JG, Hegele RA, Huff MW (2007) Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol. J Biol Chem 282:5207–5216

    Article  PubMed  CAS  Google Scholar 

  • Bhargava P, Lee CH (2012) Role and function of macrophages in the metabolic syndrome. Biochem J 442:253–262

    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 

  • Chazaud B, Brigitte M, Yacoub-Youssef H, Arnold L, Gherardi R, Sonnet C, Lafuste P, Chretien F (2009) Dual and beneficial roles of macrophages during skeletal muscle regeneration. Exerc Sport Sci Rev 37:18–22

    Article  PubMed  Google Scholar 

  • Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356

    Article  PubMed  CAS  Google Scholar 

  • de Winther MP, van Dijk KW, Havekes LM, Hofker MH (2000) Macrophage scavenger receptor class A: a multifunctional receptor in atherosclerosis. Arterioscler Thromb Vasc Biol 20:290–297

    Article  PubMed  Google Scholar 

  • Guyton JR, Klemp KF (1996) Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol 16:4–11

    Article  PubMed  CAS  Google Scholar 

  • Hope SA, Meredith IT (2003) Cellular adhesion molecules and cardiovascular disease. Part II. Their association with conventional and emerging risk factors, acute coronary events and cardiovascular risk prediction. Intern Med J 33:450–462

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM (2010) Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59:347–357

    Article  PubMed  CAS  Google Scholar 

  • Kalupahana NS, Moustaid-Moussa N, Claycombe KJ (2012) Immunity as a link between obesity and insulin resistance. Mol Aspects Med 33:26–34

    Article  PubMed  CAS  Google Scholar 

  • Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505

    Article  PubMed  CAS  Google Scholar 

  • Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF, Freeman MW (2002) Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 277:49982–49988

    Article  PubMed  CAS  Google Scholar 

  • Larrede S, Quinn CM, Jessup W, Frisdal E, Olivier M, Hsieh V, Kim MJ, van Eck M, Couvert P, Carrie A, Giral P, Chapman MJ, Guerin M, le Goff W (2009) Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler Thromb Vasc Biol 29:1930–1936

    Article  PubMed  CAS  Google Scholar 

  • Leroux A, Ferrere G, Godie V, Cailleux F, Renoud ML, Gaudin F, Naveau S, Prevot S, Makhzami S, Perlemuter G, Cassard-Doulcier AM (2012) Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol 57:141–149

    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 

  • Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB (2005) Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr 135:562–566

    PubMed  CAS  Google Scholar 

  • Ludewig B, Laman JD (2004) The in and out of monocytes in atherosclerotic plaques: balancing inflammation through migration. Proc Natl Acad Sci U S A 101:11529–11530

    Article  PubMed  CAS  Google Scholar 

  • Lusvarghi E, Bellesia L, Mucci P (1958) Osmotic resistance of white blood cells in different circulatory districts (renal, intestinal, hepatic and peripheral) in the rabbit. Blut 4:254–260

    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 (2009) Despite antiatherogenic metabolic characteristics, SCD1-deficient mice have increased inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol 29:341–347

    Article  PubMed  CAS  Google Scholar 

  • Maher JJ, Leon P, Ryan JC (2008) Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology 48:670–678

    Article  PubMed  CAS  Google Scholar 

  • Martin-Fuentes P, Garcia-Otin AL, Calvo L, Gomez-Coronado D, Civeira F, Cenarro A (2009) Atorvastatin decreases stearoyl-CoA desaturase gene expression in THP-1 macrophages incubated with oxidized LDL. Lipids 44:115–123

    Article  PubMed  CAS  Google Scholar 

  • Mauvoisin D, Mounier C (2011) Hormonal and nutritional regulation of SCD1 gene expression. Biochimie 93:78–86

    Article  PubMed  CAS  Google Scholar 

  • Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    Article  PubMed  CAS  Google Scholar 

  • Neyrinck AM, Cani PD, Dewulf EM, de Backer F, Bindels LB, Delzenne NM (2009) Critical role of Kupffer cells in the management of diet-induced diabetes and obesity. Biochem Biophys Res Commun 385:351–356

    Article  PubMed  CAS  Google Scholar 

  • Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142:687–698

    Article  PubMed  CAS  Google Scholar 

  • Parker C III, Vita JA, Freedman JE (2001) Soluble adhesion molecules and unstable coronary artery disease. Atherosclerosis 156:417–424

    Article  PubMed  CAS  Google Scholar 

  • Rahman SM, Janssen RC, Choudhury M, Baquero KC, Aikens RM, de la Houssaye BA, Friedman JE (2012) CCAAT/enhancer-binding protein beta (C/EBPbeta) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice. J Biol Chem 287:34349–34360

    Article  PubMed  CAS  Google Scholar 

  • Rull A, Camps J, Alonso-Villaverde C, Joven J (2010) Insulin resistance, inflammation, and obesity: role of monocyte chemoattractant protein-1 (or CCL2) in the regulation of metabolism. Mediators Inflamm 2010

    Google Scholar 

  • Saez F, Chabory E, Cadet R, Vernet P, Baron S, Lobaccaro JM, Drevet JR (2007) Liver X receptors and epididymal epithelium physiology. Asian J Androl 9:574–582

    Article  PubMed  CAS  Google Scholar 

  • Senanayake S, Brownrigg LM, Panicker V, Croft KD, Joyce DA, Steer JH, Puddey IB, Yeap BB (2007) Monocyte-derived macrophages from men and women with Type 2 diabetes mellitus differ in fatty acid composition compared with non-diabetic controls. Diabetes Res Clin Pract 75:292–300

    Article  PubMed  CAS  Google Scholar 

  • Sheikine Y, Hansson GK (2004) Chemokines and atherosclerosis. Ann Med 36:98–118

    Article  PubMed  CAS  Google Scholar 

  • Siriwardhana N, Kalupahana NS, Fletcher S, Xin W, Claycombe KJ, Quignard-Boulange A, Zhao L, Saxton AM, Moustaid-Moussa N (2012) n-3 and n-6 polyunsaturated fatty acids differentially regulate adipose angiotensinogen and other inflammatory adipokines in part via NF-kappaB-dependent mechanisms. J Nutr Biochem 23:1661–1667

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Hao M, Luo Y, Liang CP, Silver DL, Cheng C, Maxfield FR, Tall AR (2003) Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure. J Biol Chem 278:5813–5820

    Article  PubMed  CAS  Google Scholar 

  • Teupser D, Kretzschmar D, Tennert C, Burkhardt R, Wilfert W, Fengler D, Naumann R, Sippel AE, Thiery J (2008) Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice. Arterioscler Thromb Vasc Biol 28:2009–2015

    Article  PubMed  CAS  Google Scholar 

  • Tojo N, Asakura E, Koyama M, Tanabe T, Nakamura N (1999) Effects of macrophage colony-stimulating factor (M-CSF) on protease production from monocyte, macrophage and foam cell in vitro: a possible mechanism for anti-atherosclerotic effect of M-CSF. Biochim Biophys Acta 1452:275–284

    Article  PubMed  CAS  Google Scholar 

  • Trayhurn P, Drevon CA, Eckel J (2011) Secreted proteins from adipose tissue and skeletal muscle—adipokines, myokines and adipose/muscle cross-talk. Arch Physiol Biochem 117:47–56

    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 

  • Vedhachalam C, Liu L, Nickel M, Dhanasekaran P, Anantharamaiah GM, Lund-Katz S, Rothblat GH, Phillips MC (2004) Influence of ApoA-I structure on the ABCA1-mediated efflux of cellular lipids. J Biol Chem 279:49931–49939

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Kurdi-Haidar B, Oram JF (2004) LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J Lipid Res 45:972–980

    Article  PubMed  CAS  Google Scholar 

  • Wong BX, Kyle RA, Myhill PC, Croft KD, Quinn CM, Jessup W, Yeap BB (2011) Dyslipidemic diabetic serum increases lipid accumulation and expression of stearoyl-CoA desaturase in human macrophages. Lipids 46:931–941

    Article  PubMed  CAS  Google Scholar 

  • Yudkin JS (2007) Inflammation, obesity, and the metabolic syndrome. Horm Metab Res 39:707–709

    Article  PubMed  CAS  Google Scholar 

  • Zeyda M, Stulnig TM (2009) Obesity, inflammation, and insulin resistance—a mini-review. Gerontology 55:379–386

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Grieger JA, Kris-Etherton PM, Thompson JT, Gillies PJ, Fleming JA, Vanden Heuvel JP (2011) Walnut oil increases cholesterol efflux through inhibition of stearoyl CoA desaturase 1 in THP-1 macrophage-derived foam cells. Nutr Metab (Lond) 8:61

    Article  CAS  Google Scholar 

  • Zhang J, Kris-Etherton PM, Thompson JT, Hannon DB, Gillies PJ, Heuvel JP (2012) Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: evidence for a farnesoid-X-receptor mechanism of action. J Nutr Biochem 23:400–409

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Yin Z, Guo X, Hajjar DP, Han J (2010) Inhibition of ERK1/2 and activation of liver X receptor synergistically induce macrophage ABCA1 expression and cholesterol efflux. J Biol Chem 285:6316–6326

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka

    Nishan Sudheera Kalupahana

  2. Nutritional Sciences, Texas Tech University, Lubbock, TX, USA

    Shu Wang, Shaikh M. Rahman & Naima Moustaid-Moussa

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  1. Nishan Sudheera Kalupahana
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  2. Shu Wang
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  3. Shaikh M. Rahman
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  4. Naima Moustaid-Moussa
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Correspondence to Nishan Sudheera Kalupahana .

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

    James M. Ntambi, Ph.D.

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Kalupahana, N.S., Wang, S., Rahman, S.M., Moustaid-Moussa, N. (2013). Function and Regulation of Macrophage Stearoyl-CoA Desaturase in Metabolic Disorders. 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_6

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