Implications of Agonizing and Antagonizing Stearoyl-CoA Desaturase-1
Main Article Content
Abstract
Stearoyl-CoA Desaurase-1 (SCD1) is an enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids in various organ systems. SCD1’s role and proposed properties make it of interest for possible pharmacological intervention to help mitigate various diseases such as cancer, heart disease, liver dysfunction, diabetes, etc. Prior research on SCD1’s uses as a therapeutic agent has presented the potential for the development of compounds to act as either an agonist or antagonist. However, there is a discrepancy in the literature regarding SCD1 and its proposed uses, whether by inhibiting the enzyme or promoting its activity. A wide array of work has looked at different organ systems, inhibitors, disease state of interest, and methods of the study that included either mouse or human models. A notable trend was the incidence of a common adverse effect profile affecting the skin, the heart, adipose tissue, the liver, and the immune system. It may be possible to infer that the enzyme’s extensively documented adverse event profiles, along with the integration of SCD in various metabolic circles, and potential use of an inhibiting therapeutic agent, holds potential for future development. This suggested that whole body depletion or increase in SCD1 may cause unforeseen side effects. Further research on specific agonists and antagonists suggests that future pharmacological interventions should be organ or organ system specific to avoid unwanted side effects.
Keywords:
Stearoyl-CoA desaturase-1, SCD1, agonize, antagonize, pros, cons, cancer therapy, metabolism, liver health, inhibitor
Article Details
How to Cite
DEUTSCH, Nicholas; DOGIPARTHI, Jaswanthi; PRIEFER, Ronny.
Implications of Agonizing and Antagonizing Stearoyl-CoA Desaturase-1.
Medical Research Archives, [S.l.], v. 8, n. 12, dec. 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2269>. Date accessed: 24 apr. 2024.
doi: https://doi.org/10.18103/mra.v8i12.2269.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Ikeda J, Ichiki T, Takahara Y, et al. PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages. PLoS ONE. 2015;10(6):e0128546.
5. Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem. 2007;282(4):2483-93.
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8. Noto A, Raffa S, De vitis C, et al. Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells. Cell Death Dis. 2013;4:e947.
9. Kikuchi K, Tsukamoto H. Stearoyl-CoA desaturase and tumorigenesis. Chem Biol Interact. 2020;316:108917.
10. Du X, Wang QR, Chan E, et al. FGFR3 stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth. Cancer Res. 2012;72(22):5843-55.
11. Igal RA. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis. 2010;31(9):1509-15.
12. Qin X-Y, Kojima S. Inhibition of Stearoyl-CoA Desaturase-1 Activity Suppressed SREBP Signaling in Colon Cancer Cells and Their Spheroid Growth. Gastrointestinal Disorders. 2019; 1(1):191-200.
13. Chen L, Ren J, Yang L, et al. Stearoyl-CoA desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis. Sci Rep. 2016;6:19665.
14. Mauvoisin D, Charfi C, Lounis AM, Rassart E, Mounier C. Decreasing stearoyl-CoA desaturase-1 expression inhibits β-catenin signaling in breast cancer cells. Cancer Sci. 2013;104(1):36-42.
15. Pisanu ME, Noto A, De vitis C, et al. Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. Cancer Lett. 2017;406:93-104.
16. Tracz-gaszewska Z, Dobrzyn P. Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer. Cancers (Basel). 2019;11(7)
17. Uto Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chem Phys Lipids. 2016;197:3-12.
18. Liu L, Wang S, Yao L, et al. Long-term fructose consumption prolongs hepatic stearoyl-CoA desaturase 1 activity independent of upstream regulation in rats. Biochem Biophys Res Commun. 2016;479(4):643-648.
19. Cohen P, Miyazaki M, Socci ND, et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002;297(5579):240-3.
20. Lounis MA, Escoula Q, Veillette C, Bergeron KF, Ntambi JM, Mounier C. SCD1 deficiency protects mice against ethanol-induced liver injury. Biochim Biophys Acta. 2016;1861(11):1662-1670.
21. Gutiérrez-juárez R, Pocai A, Mulas C, et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest. 2006;116(6):1686-95.
22. Stryjecki C, Roke K, Clarke S, et al. Enzymatic activity and genetic variation in SCD1 modulate the relationship between fatty acids and inflammation. Mol Genet Metab. 2012;105(3):421-7.
23. Liu X, Miyazaki M, Flowers MT, et al. Loss of Stearoyl-CoA desaturase-1 attenuates adipocyte inflammation: effects of adipocyte-derived oleate. Arterioscler Thromb Vasc Biol. 2010;30(1):31-8.
24. Liu X, Strable MS, Ntambi JM. Stearoyl CoA desaturase 1: role in cellular inflammation and stress. Adv Nutr. 2011;2(1):15-22.
25. Kurikawa N, Takagi T, Wakimoto S, et al. A novel inhibitor of stearoyl-CoA desaturase-1 attenuates hepatic lipid accumulation, liver injury and inflammation in model of nonalcoholic steatohepatitis. Biol Pharm Bull. 2013;36(2):259-67.
26. Bednarski T, Olichwier A, Opasinska A, et al. Stearoyl-CoA desaturase 1 deficiency reduces lipid accumulation in the heart by activating lipolysis independently of peroxisome proliferator-activated receptor α. Biochim Biophys Acta. 2016;1861(12 Pt A):2029-2037.
27. Dobrzyn P, Dobrzyn A, Miyazaki M, Ntambi JM. Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice. J Lipid Res. 2010;51(8):2202-10.
28. Dobrzyn P, Sampath H, Dobrzyn A, Miyazaki M, Ntambi JM. Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart. Am J Physiol Endocrinol Metab. 2008;294(2):E357-64.
29. Brown JM, Chung S, Sawyer JK, et al. Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis. Circulation. 2008;118(14):1467-75.
30. Matsui H, Yokoyama T, Sekiguchi K, et al. Stearoyl-CoA desaturase-1 (SCD1) augments saturated fatty acid-induced lipid accumulation and inhibits apoptosis in cardiac myocytes. PLoS ONE. 2012;7(3):e33283.
31. Nakaya K, Ayaori M, Uto-kondo H, et al. Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport. Biochim Biophys Acta. 2013;1831(8):1402-11.
32. Dou, F., Chen, J., Cao, H., Jia, Q., Shen, D., Liu, T., & Chen, C. (2019). Anti-atherosclerotic effects of LXRα agonist through induced conversion of M1 macrophage to M2. American journal of translational research, 11(6), 3825–3840.
33. Peláez R, Pariente A, Pérez-sala Á, Larráyoz IM. Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases. Cells. 2020;9(1)
34. Zhang X, Liu J, Su W, et al. Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRα-SREBP1c-dependent mechanism. J Diabetes. 2014;6(3):212-20.
35. Mitro N, Vargas L, Romeo R, Koder A, Saez E. T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett. 2007;581(9):1721-6.
36. Lai KKY, Kweon SM, Chi F, et al. Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology. 2017;152(6):1477-1491.
37. Noto A, De vitis C, Pisanu ME, et al. Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. Oncogene. 2017;36(32):4671-4672.
38. Fritz V, Benfodda Z, Rodier G, et al. Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol Cancer Ther. 2010;9(6):1740-54.
39. Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003;116(Pt 7):1175-86.
40. Hawley SA, Davison M, Woods A, et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996;271(44):27879-87.
41. Li J, Condello S, Thomes-pepin J, et al. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell. 2017;20(3):303-314.e5.
42. Ran H, Zhu Y, Deng R, et al. Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN. J Exp Clin Cancer Res. 2018;37(1):54.
43. Ikeda J, Ichiki T, Takahara Y, et al. PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages. PLoS ONE. 2015;10(6):e0128546.
44. Zhang Z, Dales NA, Winther MD. Opportunities and challenges in developing stearoyl-coenzyme A desaturase-1 inhibitors as novel therapeutics for human disease. J Med Chem. 2014;57(12):5039-56.
2. Mohammadzadeh, F.; Hosseini, V.; Alihemmati, A.; Shaaker, M.; Mosayyebi, G.; Darabi, M.; Mehdizadeh, A. The Role of Stearoyl-Coenzyme A Desaturase 1 in Liver Development, Function, and Pathogenesis. jrenhep 2019, 3, 15-22.
3. Wu X, Zou X, Chang Q, et al. The evolutionary pattern and the regulation of stearoyl-CoA desaturase genes. Biomed Res Int. 2013;2013:856521.
4. Ikeda J, Ichiki T, Takahara Y, et al. PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages. PLoS ONE. 2015;10(6):e0128546.
5. Sampath H, Miyazaki M, Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. J Biol Chem. 2007;282(4):2483-93.
6. Imamura K, Tomita N, Kawakita Y, et al. Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents. Bioorg Med Chem. 2017;25(14):3768-3779.
7. Roongta UV, Lawrence RM, Wong TW, et al. Abstract C62: Cancer cell dependence on unsaturated fatty acids implicates stearoyl-coA desaturase as a target for cancer therapy. Metabolism and Autophagy. 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl)
8. Noto A, Raffa S, De vitis C, et al. Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells. Cell Death Dis. 2013;4:e947.
9. Kikuchi K, Tsukamoto H. Stearoyl-CoA desaturase and tumorigenesis. Chem Biol Interact. 2020;316:108917.
10. Du X, Wang QR, Chan E, et al. FGFR3 stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth. Cancer Res. 2012;72(22):5843-55.
11. Igal RA. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis. 2010;31(9):1509-15.
12. Qin X-Y, Kojima S. Inhibition of Stearoyl-CoA Desaturase-1 Activity Suppressed SREBP Signaling in Colon Cancer Cells and Their Spheroid Growth. Gastrointestinal Disorders. 2019; 1(1):191-200.
13. Chen L, Ren J, Yang L, et al. Stearoyl-CoA desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis. Sci Rep. 2016;6:19665.
14. Mauvoisin D, Charfi C, Lounis AM, Rassart E, Mounier C. Decreasing stearoyl-CoA desaturase-1 expression inhibits β-catenin signaling in breast cancer cells. Cancer Sci. 2013;104(1):36-42.
15. Pisanu ME, Noto A, De vitis C, et al. Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. Cancer Lett. 2017;406:93-104.
16. Tracz-gaszewska Z, Dobrzyn P. Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer. Cancers (Basel). 2019;11(7)
17. Uto Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chem Phys Lipids. 2016;197:3-12.
18. Liu L, Wang S, Yao L, et al. Long-term fructose consumption prolongs hepatic stearoyl-CoA desaturase 1 activity independent of upstream regulation in rats. Biochem Biophys Res Commun. 2016;479(4):643-648.
19. Cohen P, Miyazaki M, Socci ND, et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002;297(5579):240-3.
20. Lounis MA, Escoula Q, Veillette C, Bergeron KF, Ntambi JM, Mounier C. SCD1 deficiency protects mice against ethanol-induced liver injury. Biochim Biophys Acta. 2016;1861(11):1662-1670.
21. Gutiérrez-juárez R, Pocai A, Mulas C, et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest. 2006;116(6):1686-95.
22. Stryjecki C, Roke K, Clarke S, et al. Enzymatic activity and genetic variation in SCD1 modulate the relationship between fatty acids and inflammation. Mol Genet Metab. 2012;105(3):421-7.
23. Liu X, Miyazaki M, Flowers MT, et al. Loss of Stearoyl-CoA desaturase-1 attenuates adipocyte inflammation: effects of adipocyte-derived oleate. Arterioscler Thromb Vasc Biol. 2010;30(1):31-8.
24. Liu X, Strable MS, Ntambi JM. Stearoyl CoA desaturase 1: role in cellular inflammation and stress. Adv Nutr. 2011;2(1):15-22.
25. Kurikawa N, Takagi T, Wakimoto S, et al. A novel inhibitor of stearoyl-CoA desaturase-1 attenuates hepatic lipid accumulation, liver injury and inflammation in model of nonalcoholic steatohepatitis. Biol Pharm Bull. 2013;36(2):259-67.
26. Bednarski T, Olichwier A, Opasinska A, et al. Stearoyl-CoA desaturase 1 deficiency reduces lipid accumulation in the heart by activating lipolysis independently of peroxisome proliferator-activated receptor α. Biochim Biophys Acta. 2016;1861(12 Pt A):2029-2037.
27. Dobrzyn P, Dobrzyn A, Miyazaki M, Ntambi JM. Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice. J Lipid Res. 2010;51(8):2202-10.
28. Dobrzyn P, Sampath H, Dobrzyn A, Miyazaki M, Ntambi JM. Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart. Am J Physiol Endocrinol Metab. 2008;294(2):E357-64.
29. Brown JM, Chung S, Sawyer JK, et al. Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis. Circulation. 2008;118(14):1467-75.
30. Matsui H, Yokoyama T, Sekiguchi K, et al. Stearoyl-CoA desaturase-1 (SCD1) augments saturated fatty acid-induced lipid accumulation and inhibits apoptosis in cardiac myocytes. PLoS ONE. 2012;7(3):e33283.
31. Nakaya K, Ayaori M, Uto-kondo H, et al. Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport. Biochim Biophys Acta. 2013;1831(8):1402-11.
32. Dou, F., Chen, J., Cao, H., Jia, Q., Shen, D., Liu, T., & Chen, C. (2019). Anti-atherosclerotic effects of LXRα agonist through induced conversion of M1 macrophage to M2. American journal of translational research, 11(6), 3825–3840.
33. Peláez R, Pariente A, Pérez-sala Á, Larráyoz IM. Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases. Cells. 2020;9(1)
34. Zhang X, Liu J, Su W, et al. Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRα-SREBP1c-dependent mechanism. J Diabetes. 2014;6(3):212-20.
35. Mitro N, Vargas L, Romeo R, Koder A, Saez E. T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett. 2007;581(9):1721-6.
36. Lai KKY, Kweon SM, Chi F, et al. Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology. 2017;152(6):1477-1491.
37. Noto A, De vitis C, Pisanu ME, et al. Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. Oncogene. 2017;36(32):4671-4672.
38. Fritz V, Benfodda Z, Rodier G, et al. Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol Cancer Ther. 2010;9(6):1740-54.
39. Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003;116(Pt 7):1175-86.
40. Hawley SA, Davison M, Woods A, et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996;271(44):27879-87.
41. Li J, Condello S, Thomes-pepin J, et al. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell. 2017;20(3):303-314.e5.
42. Ran H, Zhu Y, Deng R, et al. Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN. J Exp Clin Cancer Res. 2018;37(1):54.
43. Ikeda J, Ichiki T, Takahara Y, et al. PPARγ Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages. PLoS ONE. 2015;10(6):e0128546.
44. Zhang Z, Dales NA, Winther MD. Opportunities and challenges in developing stearoyl-coenzyme A desaturase-1 inhibitors as novel therapeutics for human disease. J Med Chem. 2014;57(12):5039-56.