Abstract
Stearoyl-CoA desaturase (SCD) is a regulatory enzyme in lipogenesis, catalyzing the rate-limiting step in the overall de novo synthesis of monousaturated FA, mainly oleate and palmitoleate from stearoyl- and palmitoyl-CoA, respectively. Oleate and palmitoleate are the major monounsaturated FA of membrane phospholipids, TG, wax esters, cholesterol esters, and alkyldiacylglycerol. Several SCD gene isoforms (SCD1, SCD2, SCD3, and SCD4) exist in mice, and two have been characterized in humans. SCD1 gene expression in liver cells is regulated by numerous stimuli including diet and hormones. We are interested in why SCD is such a highly regulated enzyme even though oleate, the major product of this enzyme, is one of the most abundant FA in the diet and is therefore readily available. Dietary oleate is also well known for its TG-lowering effects and, as a major component of olive oil, is expected to have beneficial effects. However, high SCD activity has been implicated in diabetes, obesity, atherosclerosis, and cancer in several animal models; therefore, the role that de novo oleate plays in these disease states has to be carefully evaluated. By using SCD1-/-mice, which are deficient in tissue oleate, we begin to learn more about the physiological role of SCD gene expression and oleate in normal and disease states.
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Abbreviations
- ACC:
-
acetyl-CoA carboxylase
- AMPK:
-
AMP-activated protein kinase
- BAT:
-
brown adipose tissue
- CPT-1:
-
carnitine palmitoyltransferase-1
- PPARα:
-
peroxisome proliferator-activated receptor-α
- SCD:
-
stearoyl-CoA deseaturase
- SRE:
-
sterol response element
- SREBP-1c:
-
sterol regulatory element-binding protein-1c
References
Enoch, H.G., Catala, A., and Strittmatter, P. (1976) Mechanism of Rat Liver Microsomal Stearyl-CoA Desaturase. Studies of the Substrate Specificity, Enzyme-Substrate Interactions, and the Function of Lipid, J. Biol. Chem. 251, 5095–5103.
Enoch, H.G., and Strittmatter, P. (1978) Role of Tyrosyl and Arginyl Residues in Rat Liver Microsomal Stearyl Coenzyme A Desaturase, Biochemistry 17, 4927–4932.
Ntambi, J.M. (1999) Regulation of Stearoyl-CoA Desaturase by Polyunsaturated Fatty Acids and Cholesterol, J. Lipid Res. 40, 1549–1558.
Ntambi, J.M. (1995) The Regulation of Stearoyl-CoA Desaturase (SCD), Prog. Lipid Res. 34, 139–150.
Miyazaki, M., and Ntambi, J.M. (2003) Role of Stearoyl-CoA Desaturase in Lipid Metabolism, Prostaglandins Leukot. Essent. Fatty Acids 68, 113–121.
Ntambi, J.M., and Miyazaki, M. (2003) Recent Insights into Stearoyl-CoA Desaturase-1, Curr. Opin. Lipidol. 14, 255–261.
Miyazaki, M., Kim, Y.C., Gray-Keller, M.P., Attie, A.D., and Ntambi, J.M. (2000) The Biosynthesis of Hepatic Cholesterol Esters and Triglycerides Is Impaired in Mice with a Disruption of the Gene for Stearoyl-CoA Desaturase 1, J. Biol. Chem. 275, 30132–30138.
Miyazaki, M., Man, W.C., and Ntambi, J.M. (2001) Targeted Disruption of Stearoyl-CoA Desaturase 1 Gene in Mice Causes Atrophy of Sebaceous and Meibomian Glands and Depletion of Wax Esters in the Eyclid, J. Nutr. 131, 2260–2268.
Miyazaki, M., Kim, H.J., Man, W.C., and Ntambi, J.M. (2001) Oleoyl-CoA Is the Major de novo Product of Stearoyl-CoA Desaturase 1 Gene Isoform and Substrate for the Biosynthesis of the Harderian Gland 1-Alkyl-2,3-diacylglycerol, J. Biol. Chem. 276, 39455–39461.
Miyazaki, M., Kim, Y.C., and Ntambi, J.M. (2001) A Lipogenic Diet in Mice with a Disruption of the Stearoyl-CoA Desaturase 1 Gene Reveals a Stringent Requirement of Endogenous Monounsaturated Fatty Acids for Triglyceride Synthesis, J. Lipid Res. 42, 1018–1024.
Velasco, A., Tabernero, A., and Medina, J.M. (2003) Role of Oleic Acid as a Neurotrophic Factor Is Supported in vivo by the Expression of GAP-43 Subsequent to the Activation of SREBP-1 and the Up-regulation of Stearoyl-CoA Desaturase During Postnatal Development of the Brain, Brain Res. 977, 103–111.
Medina, J.M., and Tabernero, A. (2002) Astrocyte-Synthesized Oleic Acid Behaves as a Neurotrophic Factor for Neurons, J. Physiol. Paris 96, 265–271.
Tabernero, A., Lavado, E.M., Granda, B., Velasco, A., and Medina, J.M. (2001) Neuronal Differentiation Is Triggered by Oleic Acid Synthesized and Released by Astrocytes, J. Neurochem. 79, 606–616.
Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G., and Rossetti, L. (2002) Central Administration of Oleic Acid Inhibits Glucose Production and Food Intake, Diabetes 51, 271–275.
Listenberger, L.L., Han, X., Lewis, S.E., Cases, S., Farese, R.V., Ory, D.S., Jr., and Schaffer, J.E. (2003) Triglyceride Accumulation Protects Against Fatty Acid-Induced Lipotoxicity, Proc. Natl. Acad. Sci. USA 100, 3077–3082.
Hardy, S., Langelier, Y., and Prentki, M. (2000) Oleate Activates Phosphatidylinositol 3-Kinase and Promotes Proliferation and Reduces Apoptosis of MDA-MB-231 Breast Cancer Cells, Whereas Palmitate Has Opposite Effects, Cancer Res. 60, 6353–6358.
Ntambi, J.M., Buhrow, S.A., Kaestner, K.H., Christy, R.J., Sibley, E., Kelly, T.J., Jr., and Lane, M.D. (1988) Differentiation-Induced Gene Expression in 3T3-L1 Preadipocytes. Characterization of a Differentially Expressed Gene Encoding Stearoyl-CoA Desaturase, J. Biol. Chem. 263, 17291–17300.
Kaestner, K.H., Ntambi, J.M., Kelly, T.J., Jr., and Lane, M.D. (1989) Differentiation-Induced Gene Expression in 3T3-L1 Preadipocytes. A Second Differentially Expressed Gene Encoding Stearoyl-CoA Desaturase, J. Biol. Chem. 264, 14755–14761.
Miyazaki, M., Jacobson, M.J., Man, W.C., Cohen, P., Asilmaz, E., Friedman, J.M., and Ntambi, J.M. (2003) Identification and Characterization of Murine SCD4: A Novel Heart-Specific Stearoyl-CoA Desaturase Isoform Regulated by Leptin and Dietary Factors, J. Biol. Chem. 278, 33904–33911.
Mihara, K. (1990) Structure and Regulation of Rat Liver Microsomal Stearoyl-CoA Desaturase Gene, J. Biochem. (Tokyo) 108, 1022–1029.
Zhang, L., Ge, L., Parimoo, S., Stenn, K., and Prouty, S.M. (1999) Human Stearoyl-CoA Desaturase: Alternative Transcripts Generated from a Single Gene by Usage of Tandem Polyadenylation Sites, Biochem. J. 340, 255–264.
Beiraghi, S., Zhou, M., Talmadge, C.B., Went-Sumegi, N., Davis, J.R., Huang, D., Saal, H., Seemayer, T.A., and Sumegi, J. (2003) Identification and Characterization of a Novel Gene Disrupted by a Pericentric Inversion inv(4)(p13.1q21.1) in a Family with Cleft Lip, Gene 309, 11–21.
Tabor, D.E., Xia, Y.R., Mehrabian, M., Edwards, P.A., and Lusis, A.J. (1998) A Cluster of Stearoyl CoA Desaturase Genes, Scd1 and Scd2, on Mouse Chromosome 19, Mamm. Genome 9, 341–342.
Miyazaki, M., Gomez, F.E., and Ntambi, J.M. (2002) Lack of Stearoyl-CoA Desaturase-1 Function Induces a Palmitoyl-CoA Δ6 Desaturase and Represses the Stearoyl-CoA Desaturase-3 Gene in the Preputial Glands of the Mouse, J. Lipid Res. 43, 2146–2154.
Ntambi, J.M. (1992) Dietary Regulation of Stearoyl-CoA Desaturase 1 Gene Expression in Mouse Liver, J. Biol. Chem. 267, 10925–10930.
Waters, K., and Ntambi, J.M. (1994) Insulin and Dietary Fructose Induce Stearoyl-CoA Desaturase 1 Gene Expression in Liver of Diabetic Mice, J. Biol. Chem. 269, 27773–27777.
Repa, J.J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J.M., Shimomura, I., Shan, B., Brown, M.S., Goldstein, J.L., and Mangelsdorf, D.J. (2000) Regulation of Mouse Sterol Regulatory Element-Binding Protein-1c Gene (SREBP-1c) by Oxysterol Receptors, LXR-α and LXR-β, Genes. Dev. 14, 2819–2830.
Landau, J.M., Sekowski, A., and Hamm, M.W. (1997) Dietary Cholesterol and the Activity of Stearoyl CoA Desaturase in Rats: Evidence for an Indirect Regualtory Effect, Biochim. Biophys. Acta 1345, 349–357.
Kim, H.J., Miyazaki, M., and Ntambi, J.M. (2002) Dietary Cholesterol Opposes PUFA-Mediated Repression of the stearoyl-CoA Desaturase-1 Gene by SREBP-1 Independent Mechanism, J. Lipid Res. 43, 1750–1757.
Miller, C.W., Waters, K.M., and Ntambi, J.M. (1997) Regulation of Hepatic Stearoyl-CoA Desaturase Gene 1 by Vitamin A, Biochem. Biophys. Res. Commun. 231, 206–210.
Samuel, W., Kutty, R.K., Nagineni, S., Gordon, J.S., Prouty, S.M., Chandraratna, R.A., and Wiggert, B. (2001) Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid, J. Biol. Chem. 276, 28744–28750.
Miller, C.W. and Ntambi, J.M. (1996) Peroxisome Proliferators Induce Mouse Liver Stearoyl-CoA Desaturase 1 Gene Expression, Proc. Natl. Acad. Sci. USA 93, 9443–9448.
Waters, K.M., Miller, C.W., and Ntambi, J.M. (1997) Localization of a Negative Thyroid Hormone-Response Region in Hepatic Stearoyl-CoA Desaturase Gene 1, Biochem. Biophys. Res. Commun. 233, 838–843.
Waters, K.M., and Ntambi, J.M. (1996) Polyunsaturated Fatty Acids Inhibit Hepatic Stearoyl-CoA Desaturase-1 Gene in Diabetic Mice, Lipids 31, S33-S36.
Kurebayashi, S., Hirose, T., Miyashita, Y., Kasayama, S., and Kishimoto, T. (1997) Thiazolidinediones Downregulate Stearoyl-CoA Desaturase 1 Gene Expression in 3T3-L1 Adipocytes, Diabetes 46, 2115–2118.
Kim, Y.-C., Gomez, E., Fox, B.G., and Ntambi, J.M. (2000) Differential Regulation of the Stearoyl-CoA Desaturase Genes by Thiazolidinediones in 3T3-L1 Adipocytes, J. Lipid Res. 41, 1310–1316.
Cohen, P., Miyazaki, M., Socci, N.D., Hagge-Greenberg, A. Liedtke, W., Soukas, A.A., Sharma, R., Hudgins, L.C., Ntambi, J.M., and Friedman, J.M. (2002) Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss, Science 297, 240–243.
Garbay, B., Boiron-Sargueil, C., Shy, M., Chbihi, T., Jiang, H., Kamholz, J., and Cassagne, C. (1998) Regulation of Oleoyl-CoA Synthesis in the Peripheral Nervous System: Demonstration of a Link with Myelin Synthesis, J. Neurochem. 71, 1719–1726.
Tebbey, P.W., and Buttke, T.M. (1992) Stearoyl-CoA Desaturase Gene Expression in Lymphocytes, Biochem. Biophys. Res. Commun. 186, 531–536.
Buttke, T.M., Van Cleave, S., Steelman, L., and McCubrey, J.A. (1989) Absence of Unsaturated Fatty Acid Synthesis in Murine T Lymphocytes, Proc. Natl. Acad. Sci. USA 86, 6133–6137.
Zheng, Y., Prouty, S.M., Harmon, A., Sundberg, J.P., Stenn, K.S., and Parimoo, S. (2001) SCD3—A Novel Gene of the Stearoyl-CoA Desaturase Familywith Restricted Expression in Skin, Genomics 71, 182–191.
Ntambi, J.M., Miyazaki, M., Stoehr, J.P., Lan, H., Kendziorski, C.M., Yandell, B.S., Song, Y., Cohen, P., Friedman, J.M., and Attie, A.D. (2002) Loss of Stearoyl-CoA Desaturase-1 Function Protects Mice Against Adiposity, Proc. Natl. Acad. Sci. USA 99, 11482–11486.
Lee, S.H., Dobrzyn, A., Dobrzyn, P., Rahman, S.M., Miyazaki, M., Ntambi, J.M. (2004) Lack of Stearoyl-CoA Desaturase 1 Upregulates Basal Thermogenesis but Causes Hypothermia in a Cold Environment, J. Lipid Res. 45, 1674–1682.
Attie, A.D., Krauss, R.M., Gray-Keller, M.P., Brownlie, A., Miyazaki, M., Kastelein, J.J., Lusis, J.J., Stalenhoef, A.F.H., Stoehr, J.P., Hayden, M.R., and Ntambi J.M. (2002) Plasma Triglycerides in Human and Mouse Hypertriglyceridemia, J. Lipid Res. 43, 1899–1907.
Osborne, T.F. (2000) Sterol Regulatory Element-Binding Proteins (SREBPs): Key Regulators of Nutritional Homeostasis and Insulin Action, J. Biol. Chem. 275, 32379–32382.
Miyazaki, M., Dobrzyn, A., Sampath, H., Lee, S.H., Man, W.C., Chu, K., Peters, J.M., Gonzalez, F.J., and Ntambi, J.M. (2004) Reduced Adiposity and Liver Steatosis by Stearoyl-CoA Desaturase Deficiency Are Independent of Peroxisome Proliferator-Activated Receptor-α, J. Biol. Chem. 279, 35017–35024.
Hannah, V.C., Ou, J., Luong, A., Goldstein, J.L., and Brown, M.S. (2001) Unsaturated Fatty Acids Down-regulate SREBP Isoforms 1a and 1c by Two Mechanisms in HEK-293 Cells, J. Biol. Chem., 276, 4365–4372.
Xu, J., Teran-Garcia, M., Park, J.H., Nakamura, M.T., and Clarke, S.D., (2001) Sterol Regulatory Element Binding Protein-1 Expression Is Suppressed by Polyunsaturated Fatty Acids. A Mechanism for the Coordinate Suppression of Lipogenic Genes by Polyunsaturated Fats, J. Biol. Chem. 276, 9800–9807.
Kersten, S., Seydoux, J., Peters, J.M., Gonzalez, F.J. Desvergne, B., and Wahli, W. (1999) Peroxisome Proliferator-Activated Receptor α Mediates the Adaptive Response to Fasting, J. Clin. Invest. 103, 1489–1498.
Kersten, S., Mandard, S., Tan, N.S., Escher, P., Metzger, D., Chambon, P., Gonzalez, F.J., Desvergne, B., and Wahli, W. (2000) Characterization of the Fasting-Induced Adipose Factor FIAF, a Novel Peroxisome Proliferator-Activated Receptor Target Gene, J. Biol. Chem. 275, 28488–28493.
Varanasi, U., Chu, R., Huang, Q., Castellon, R., Yeldandi, A.V., and Reddy, J.K. (1996) Identification of a Peroxisome Proliferator-Responsive Element Upstream of the Human Peroxisomal Fatty Acyl Coenzyme A Oxidase Gene, J. Biol. Chem. 271, 2147–2155.
Tugwood, J.D., Issemann, I., Anderson, R.G., Bundell, K.R., McPheat, W.L., and Green, S. (1992) The Mouse Peroxisome Proliferator Activated Receptor Recognizes a Response Element in the 5′ Flanking Sequence of the Rat Acyl-CoA Oxidase Gene, Embo. J. 11, 433–439.
Mascaro, C., Acosta, E., Ortiz, J.A., Rodriguez, J.C., Marrero, P.F., Hegardt, F.G., and Haro, D. (1999) Characterization of a Response Element for Peroxisomal Proliferator Activated Receptor (PPRE) in Human Muscle-Type Carnitine Palmitoyltransferase I, Adv. Exp. Med. Biol. 466, 79–85.
Minokoshi, Y., Kim, Y.B., Peroni, O.D., Fryer, L.G.D., Müller, C., Carling, D., and Kahn, B.B. (2002) Leptin Stimulates Fatty-Acid Oxidation by Activating AMP-Activated Protein Kinase, Nature 415, 339–343.
Dobrzyn, P., Dobrzyn, A., Miyazaki, M., Cohen, P., Asilmaz, E., Hardie, G.D., Friedman, J.M., and Ntambi, J.M. (2004) Stearoyl-CoA Desaturase-1 (SCD1) Deficiency Increases Fatty Acid Oxidation by Activating AMP-Activated Protein Kinase in Liver, Proc. Natl. Acad. Sci. USA 101, 6409–6414.
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., et al. (2002) Adiponectin Stimulates Glucose Utilization and Fatty-Acid Oxidation by Activating AMP-Activated Protein Kinase, Nat. Med. 8, 1–8.
Dobrzyn, A., and Ntambi, J.M. (2004) The Role of Stearoyl-CoA Desaturase in Body Weight Regulation, Trends Cardiovasc. Med. 14, 77–81.
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Ntambi, J.M., Miyazaki, M. & Dobrzyn, A. Regulation of stearoyl-CoA desaturase expression. Lipids 39, 1061–1065 (2004). https://doi.org/10.1007/s11745-004-1331-2
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DOI: https://doi.org/10.1007/s11745-004-1331-2