Function and Regulation of Macrophage Stearoyl-CoA Desaturase in Metabolic Disorders
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.
KeywordsCholesterol Obesity Migration Foam Triglyceride
- 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 118:1467–1475PubMedCrossRefGoogle 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 30:24–30PubMedCrossRefGoogle 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 277:49982–49988PubMedCrossRefGoogle 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 29:1930–1936PubMedCrossRefGoogle 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 57:141–149PubMedCrossRefGoogle 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 29:341–347PubMedCrossRefGoogle 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 2010Google 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 75:292–300PubMedCrossRefGoogle 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 23:1661–1667PubMedCrossRefGoogle 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 28:2009–2015PubMedCrossRefGoogle 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 1452:275–284PubMedCrossRefGoogle 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 23:400–409PubMedCrossRefGoogle Scholar