Journal articles on the topic 'SCD1'
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1
Levitsky, A., A. Gozhenko, V. Velichko, and I. Selivanskaya. "The effect of dietary fat supplements on the activity of palmitic and stearic acid desaturases based on the results of a study of the fatty acid composition of neutral lipids in blood serum and liver of rats receiving a fat-free diet." Journal of Education, Health and Sport 12, no. 1 (January 18, 2022): 197–206. http://dx.doi.org/10.12775/jehs.2022.12.01.016.
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Background. Desaturase enzymes are involved in the formation of monoenoic acids from saturated fatty acids. One such enzyme is stearyl-CoA-desaturase (SCD1), which converts stearic acid to oleic acid. The aim of this work was to determine the effect of edible fats with different fatty acid compositions on SCD1 activity.
Methods. High linoleic sunflower oil (HLSO), high oleic sunflower oil (HOSO) and palm oil (PO) were used. The rats were fed for 30 days with a semi-synthetic diet that did not contain any fats (FFD) and fat diets containing 5 % of each of the above oils. In animals, lipids were extracted from serum and liver and divided into 3 fractions: neutral lipids (NL), phospholipids (PL), and free fatty acids (FFA).
The fatty acid composition of each fraction was determined by gas chromatography. The SCD18 activity was determined by the C18:1 n-9/C18:0 ‒ ratio, and the SCD16 activity was determined by the C16:1 n-7/C16:0 ratio.
Results. A higher activity of SCD16 and SCD18 was found in the NL fraction, and the activity of SCD18 significantly exceeds that of SCD16. A decrease in the content of C16:0, C16:1 and C18:0 in the NL fraction of the liver and blood serum was shown. The activity of SCD16 in blood serum and liver decreases in rats fed fat diets, while the activity of SCD18 does not decrease, and even increases with the consumption of HOSO.
Conclusions. To determine the SCD1 activity, it is advisable to use the C18:1/C18:0 ratio in terms of the level of fatty acids in the NL fraction. Fatty diet inhibits SCD16 activity, and consumption of HOSO increases SCD18 activity.
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Li, Ying-chun, Chang-rung Chen, and Eric C. Chang. "Fission Yeast Ras1 Effector Scd1 Interacts With the Spindle and Affects Its Proper Formation." Genetics 156, no. 3 (November 1, 2000): 995–1004. http://dx.doi.org/10.1093/genetics/156.3.995.
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Abstract Ras1 GTPase is the Schizosaccharomyces pombe homolog of the mammalian Ha-Ras proto-oncoprotein. Ras1 interacts with Scd1 (aka Ral1), a presumptive guanine nucleotide exchange factor for Cdc42sp, to control organization of the cytoskeleton. In this study, we demonstrated that the scd1 deletion (scd1Δ) induced hypersensitivity to microtubule destabilizing drugs and instability of the minichromosome. Overexpression of scd1 induced formation of abnormal spindles and chromosome missegregation. The scd1 deletion worsened the defects of spindle formation in tubulin mutants; by contrast, it did not induce lethality in mutants defective in the spindle pole bodies. These genetic data suggest that Scd1 can interact with tubulin with substantial specificity to affect proper spindle formation and chromosome segregation. Subcellular localization data further illustrated that a GFP-Scd1 fusion protein can associate with the spindle. Finally, we showed that unlike ras1Δ and scd1Δ, byr2Δ (affecting the Ras1 effector for mating) is not synthetically lethal with the tubulin mutations. These data collectively suggest that the Ras1 pathway can impinge upon microtubules through Scd1, but not Byr2, to affect proper spindle formation and chromosome segregation.
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Li, Yingchun, and Eric C. Chang. "Schizosaccharomyces pombeRas1 Effector, Scd1, Interacts With Klp5 and Klp6 Kinesins to Mediate Cytokinesis." Genetics 165, no. 2 (October 1, 2003): 477–88. http://dx.doi.org/10.1093/genetics/165.2.477.
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AbstractFission yeast Scd1 is an exchange factor for Cdc42 and an effector of Ras1. In a screen for scd1 interacting genes, we isolated klp5 and klp6, which encode presumptive kinesins. Klp5 and Klp6 form a complex to control the same processes, which so far include microtubule dynamics and chromosome segregation. We showed that klp5 or klp6 inactivation in combination with the scd1 deletion (scd1Δ) created a synthetic temperature-dependent growth defect. Further genetic analysis demonstrated that Klp5 and Klp6 interacted specifically with the Ras1-Scd1 pathway, but not with the Ras1-Byr2 pathway. In addition, Klp5 and Klp6 can stably associate with Scd1 and Cdc42. A deletion in the Scd1 C terminus, which contains the PB1 domain, prevented Scd1 binding to Klp5/6 and caused a growth defect in Klp5/6 mutant cells that is indistinguishable from that induced by scd1Δ. Analysis of the double-mutant phenotype indicated that at the nonpermissive temperature, cells failed to undergo cytokinesis efficiently. These cells contained abnormal contractile rings in which F-actin and Mid1, a key regulator of F-actin ring formation and positioning, are mispositioned and fragmented. These data suggest that Klp5/6 cooperate with the Ras1-Scd1 pathway to influence proper formation of the contractile ring for cytokinesis.
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Mnatsakanyan, Hayk, Caline Pechdimaljian, Roshani Jha, Alessandro Sammarco, Baolong Su, Kevin J. Williams, Steven J. Bensinger, and Christian E. Badr. "CSIG-17. SCD5 PROTECTS GLIOBLASTOMA STEM CELLS FROM DEATH AND DIFFERENTIATION BY MODULATING INTRACELLULAR LIPID COMPOSITION." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii42. http://dx.doi.org/10.1093/neuonc/noac209.166.
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Abstract Glioblastoma (GBM) is the most common malignant brain cancer in adults, enriched in a small subpopulation of glioma stem cells (GSC), which can drive tumor recurrence and therapeutic resistance. Considerable evidence suggests that the endogenous levels of unsaturated fatty acids (FA) are crucial regulators of GSCs survival and self-renewal. Stearoyl-CoA desaturase-1 (SCD-1) is the most abundant desaturase in humans. We have previously shown that SCD1 activity is required for GSCs self-renewal and brain tumor initiation. However, SCD1 orthologous isoform, SCD5, has been poorly characterized and its potential role in GBM has not been previously reported. We have observed that SCD5 is highly enriched in GSC both at the mRNA and protein levels. Genetic downregulation of SCD5 in GSCs led to a remarkable decrease in stem cell markers, impaired cell viability and the ability to form neurospheres. Further, the downregulation of SCD5 in GSCs orthotopically implanted in mice resulted in delayed tumor growth and extended overall survival. Shotgun lipidomics in GSCs after either SCD1 or SCD5 knock-down revealed a largely distinctive lipidome profile, highlighting the divergent role of these two isoforms in GBM lipid metabolism. Surprisingly, lipidomics analysis showed that both SCD1 and SCD5 are required to synthesize a variety of lipid species involved in receptor tyrosine kinase (RTKs) and GPCRs signal transduction, directly linking FA synthesis with the oncogenic signaling. We confirmed these results by immunoblot analysis. Using specific tagging and immunofluorescence analysis, we observed that, despite a spatial overlap in SCD1 and SCD5 expression, SCD5 is uniquely present in some subcellular locations. This suggests that different functions of these isoforms could be related to different subcellular localization. Altogether, our results underscore a novel function of SCD isoforms in GSCs metabolism and highlight SCD5 as a potential therapeutic target for GBM.
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Chu, Kiki, Makoto Miyazaki, Weng Chi Man, and James M. Ntambi. "Stearoyl-Coenzyme A Desaturase 1 Deficiency Protects against Hypertriglyceridemia and Increases Plasma High-Density Lipoprotein Cholesterol Induced by Liver X Receptor Activation." Molecular and Cellular Biology 26, no. 18 (September 15, 2006): 6786–98. http://dx.doi.org/10.1128/mcb.00077-06.
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ABSTRACT Stearoyl-coenzyme A desaturase (SCD) is the rate-limiting enzyme necessary for the biosynthesis of monounsaturated fatty acids. In this study, we investigated the regulation of mouse SCD1 by liver X receptor (LXR) and its role in plasma lipoprotein metabolism upon LXR activation. In vivo, the SCD1 gene remained induced upon LXR activation in the absence of sterol regulatory element-binding protein 1c (SREBP-1c), a known transcriptional regulator of SCD1. Serial deletion and point mutation analyses in reporter gene assays, as well as a gel mobility shift assay, identified an LXR response element in the mouse SCD1 promoter. In addition, SCD1 deficiency prevented the hypertriglyceridemic effect and reduced hepatic triglyceride accumulation associated with LXR activation despite induced hepatic expression of SREBP-1c protein and several SREBP1c and LXR target genes involved in lipoprotein metabolism. Unlike wild-type mice, SCD1-deficient mice failed to elevate the hepatic triglyceride monounsaturated acid (MUFA)/saturated fatty acid (SFA) ratio despite induction of the SCD2 gene. Together, these findings suggest that SCD1 plays a pivotal role in the regulation of hepatic and plasma triglyceride accumulation, possibly by modulating the MUFA-to-SFA ratio. In addition, SCD1 deficiency also increased plasma high-density lipoprotein cholesterol levels induced by LXR activation.
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Wei, Bin, Brian S. Hercyk, Nicholas Mattson, Ahmad Mohammadi, Julie Rich, Erica DeBruyne, Mikayla M. Clark, and Maitreyi Das. "Unique spatiotemporal activation pattern of Cdc42 by Gef1 and Scd1 promotes different events during cytokinesis." Molecular Biology of the Cell 27, no. 8 (April 15, 2016): 1235–45. http://dx.doi.org/10.1091/mbc.e15-10-0700.
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The Rho-family GTPase Cdc42 regulates cell polarity and localizes to the cell division site. Cdc42 is activated by guanine nucleotide exchange factors (GEFs). We report that Cdc42 promotes cytokinesis via a unique spatiotemporal activation pattern due to the distinct action of its GEFs, Gef1 and Scd1, in fission yeast. Before cytokinetic ring constriction, Cdc42 activation, is Gef1 dependent, and after ring constriction, it is Scd1 dependent. Gef1 localizes to the actomyosin ring immediately after ring assembly and promotes timely onset of ring constriction. Gef1 is required for proper actin organization during cytokinesis, distribution of type V myosin Myo52 to the division site, and timely recruitment of septum protein Bgs1. In contrast, Scd1 localizes to the broader region of ingressing membrane during cytokinetic furrowing. Scd1 promotes normal septum formation, and scd1Δ cells display aberrant septa with reduced Bgs1 localization. Thus we define unique roles of the GEFs Gef1 and Scd1 in the regulation of distinct events during cytokinesis. Gef1 localizes first to the cytokinetic ring and promotes timely constriction, whereas Scd1 localizes later to the ingressing membrane and promotes septum formation. Our findings are consistent with reports that complexity in GTPase signaling patterns enables exquisite precision over the control of cellular processes.
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Lamas, Iker, Nathalie Weber, and Sophie G. Martin. "Activation of Cdc42 GTPase upon CRY2-Induced Cortical Recruitment Is Antagonized by GAPs in Fission Yeast." Cells 9, no. 9 (September 12, 2020): 2089. http://dx.doi.org/10.3390/cells9092089.
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The small GTPase Cdc42 is critical for cell polarization in eukaryotic cells. In rod-shaped fission yeast Schizosaccharomyces pombe cells, active GTP-bound Cdc42 promotes polarized growth at cell poles, while inactive Cdc42-GDP localizes ubiquitously also along cell sides. Zones of Cdc42 activity are maintained by positive feedback amplification involving the formation of a complex between Cdc42-GTP, the scaffold Scd2, and the guanine nucleotide exchange factor (GEF) Scd1, which promotes the activation of more Cdc42. Here, we use the CRY2-CIB1 optogenetic system to recruit and cluster a cytosolic Cdc42 variant at the plasma membrane and show that this leads to its moderate activation also on cell sides. Surprisingly, Scd2, which binds Cdc42-GTP, is still recruited to CRY2-Cdc42 clusters at cell sides in individual deletion of the GEFs Scd1 or Gef1. We show that activated Cdc42 clusters at cell sides are able to recruit Scd1, dependent on the scaffold Scd2. However, Cdc42 activity is not amplified by positive feedback and does not lead to morphogenetic changes, due to antagonistic activity of the GTPase activating protein Rga4. Thus, the cell architecture is robust to moderate activation of Cdc42 at cell sides.
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Kelly, Felice D., and Paul Nurse. "Spatial control of Cdc42 activation determines cell width in fission yeast." Molecular Biology of the Cell 22, no. 20 (October 15, 2011): 3801–11. http://dx.doi.org/10.1091/mbc.e11-01-0057.
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The fission yeast Schizosaccharomyces pombe is a rod-shaped cell that grows by linear extension at the cell tips, with a nearly constant width throughout the cell cycle. This simple geometry makes it an ideal system for studying the control of cellular dimensions. In this study, we carried out a near-genome-wide screen for mutants wider than wild-type cells. We found 11 deletion mutants that were wider; seven of the deleted genes are implicated in the control of the small GTPase Cdc42, including the Cdc42 guanine nucleotide exchange factor (GEF) Scd1 and the Cdc42 GTPase-activating protein (GAP) Rga4. Deletions of rga4 and scd1 had additive effects on cell width, and the proteins localized independently of one another, with Rga4 located at the cell sides and Scd1 at the cell tips. Activated Cdc42 localization is altered in rga4Δ, scd1Δ, and scd2Δ mutants. Delocalization and ectopic retargeting experiments showed that the localizations of Rga4 and Scd1 are crucial for their roles in determining cell width. We propose that the GAP Rga4 and the GEF Scd1 establish a gradient of activated Cdc42 within the cellular tip plasma membrane, and it is this gradient that determines cell growth-zone size and normal cell width.
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Papadaki, Piyi, Véronique Pizon, Brian Onken, and Eric C. Chang. "Two Ras Pathways in Fission Yeast Are Differentially Regulated by Two Ras Guanine Nucleotide Exchange Factors." Molecular and Cellular Biology 22, no. 13 (July 1, 2002): 4598–606. http://dx.doi.org/10.1128/mcb.22.13.4598-4606.2002.
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ABSTRACT How a given Ras prreotein coordinates multiple signaling inputs and outputs is a fundamental issue of signaling specificity. Schizosaccharomyces pombe contains one Ras, Ras1, that has two distinct outputs. Ras1 activates Scd1, a presumptive guanine nucleotide exchange factor (GEF) for Cdc42, to control morphogenesis and chromosome segregation, and Byr2, a component of a mitogen-activated protein kinase cascade, to control mating. So far there is only one established Ras1 GEF, Ste6. Paradoxically, ste6 null (ste6Δ) mutants are sterile but normal in cell morphology. This suggests that Ste6 specifically activates the Ras1-Byr2 pathway and that there is another GEF capable of activating the Scd1 pathway. We thereby characterized a potential GEF, Efc25. Genetic data place Efc25 upstream of the Ras1-Scd1, but not the Ras1-Byr2, pathway. Like ras1Δ and scd1Δ, efc25Δ is synthetically lethal with a deletion in tea1, a critical element for cell polarity control. Using truncated proteins, we showed that the C-terminal GEF domain of Efc25 is essential for function and regulated by the N terminus. We conclude that Efc25 acts as a Ras1 GEF specific for the Scd1 pathway. While ste6 expression is induced during mating, efc25 expression is constitutive. Moreover, Efc25 overexpression renders cells hyperelongated and sterile; the latter can be rescued by activated Ras1. This suggests that Efc25 can recruit Ras1 to selectively activate Scd1 at the expense of Byr2. Reciprocally, Ste6 overexpression can block Scd1 activation. We propose that external signals can partly segregate two Ras1 pathways by modulating GEF expression and that GEFs can influence how Ras is coupled to specific effectors.
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Hirota, Kouji, Kayoko Tanaka, Kunihiro Ohta, and Masayuki Yamamoto. "Gef1p and Scd1p, the Two GDP-GTP Exchange Factors for Cdc42p, Form a Ring Structure that Shrinks during Cytokinesis inSchizosaccharomyces pombe." Molecular Biology of the Cell 14, no. 9 (September 2003): 3617–27. http://dx.doi.org/10.1091/mbc.e02-10-0665.
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Fission yeast Cdc42p, a small GTPase of the Rho family, is essential for cell proliferation and maintenance of the rod-like cell morphology. Scd1/Ral1p is a GDP-GTP exchange factor (GEF) for Cdc42p. This study and a parallel study by others establish that Gef1p is another GEF for Cdc42p. Deletions of gef1 and scd1 are synthetically lethal, generating round dead cells, and hence mimic the phenotype of cdc42 deletion. Gef1p is localized mainly to the cell division site. Scd1p is also there, but it is also detectable in other parts of the cell, including the nucleus, growing ends, and the tips of conjugation tubes. Gef1p and Scd1p form a ring structure at the cell division site, which shrinks during cytokinesis following the contraction of the actomyosin ring. Formation of the Gef1p/Scd1p ring apparently depends on the integrity of the actomyosin ring. In turn, recruitment of Cdc42p to the cell division site follows the shrinking Gef1p/Scd1p ring; the Cdc42p accumulates like a closing iris. These observations suggest that Gef1p and Scd1p may have a role in mediating between contraction of the actomyosin ring and formation of the septum, by recruiting active Cdc42p to the septation site.
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Zhang, Lumin, Tomohiro Yamasaki, Tyrone Dowdy, Adrian Lita, Mark Gilbert, and Mioara Larion. "CSIG-40. STEAROYL-COA DESATURASE 1 (SCD1) IS REQUIRED FOR WNT SIGNALING TO INDUCE AN APOPTOSIS IN IDH MUTANT GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii47—vii48. http://dx.doi.org/10.1093/neuonc/noac209.189.
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Abstract BACKGROUND AND HYPOTHESES SCD1, a major enzyme of saturated fatty acids, has been implicated to be important for tumor metabolic reprograming. Our previous study show that a high level of SCD1 mRNA is associated with IDH1mut lower grade gliomas. IDH1mut glioma cells are more sensitive to SFA induced apoptosis. However, the underlying mechanism remains unclear. In this study, we investigate the functions of SCD1 in IDHmut glioma and the potential contribution of SCD1 for cancer therapy of glioma. STUDY DESIGN AND METHODS The genetically engineered IDH wild-type, IDHmut and patient derived glioma cell lines were used to evaluate SCD1 functions. The expression of proteins were checked by Western-blotting assay. SCD1 was silenced by CRISPR or siRNA. The transcriptome change after SCD1 knockdown was profiled by RNA-seq or single cell RNA-seq (scRNA-seq). RESULTS AND CONCLUSIONS SCD1 transient silencing slowed down the cell growth, suggesting that SCD1 may possess an oncogenic property. RNA-seq analysis revealed that SCD1 inhibition decreased the expression of wnt-signaling pathway genes in IDH-1mut cells. scRNA confirmed that CRISPR SCD1 significantly decreased wnt signaling in the patient cell line Ts603. Therefore, we activated wnt pathway using a small chemical compound, BML-2838. Consistent with recent studies, wnt pathway induction led to a dramatically suppression of glioma cells growth. However, SCD1 silencing reversed this inhibitory effect. Further investigation revealed that SCD1 inhibition reduced the nucleus translocation of phosphorylated beta-catenin. Overall, the results suggest that SCD1 is vital for the onset of wnt pathway in glioma cells. High level of SCD1 expression may render the IDHmut glioma cells more sensitive to wnt pathway induced apoptosis. RELEVANCE AND IMPORTANCE In clinical, the 5-years survival rate of glioma remains low. SCD1 have been considered as a target for glioma therapy, recently. Our data provides a new insight on the strategy to target SCD1 in clinical.
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Yadav, Sarita Ramsaran, Mangala Lakshmi Ragavan, Sanjeeb Kumar Mandal, and Nilanjana Das. "DEGRADATION OF AZO DYE AND ELECTRICITY GENERATION USING YEAST MEDIATED MICROBIAL FUEL CELL." Fungal Territory 1, no. 1 (August 9, 2018): 1–4. http://dx.doi.org/10.36547/ft.2018.1.1.1-4.
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In the present study, the efficiency of yeast mediated microbial fuel cell (MFC) was investigated towards degradation of Trypan blue (azo dye) and electricity generation. Five yeast strains viz. SC1, SC2, SCD1, SCD2, and SCD3 were isolated from different sources. The internal resistance of yeast isolates was tested using ferric oxide reduction method. To maximize the power density of MFC, NaCl was added to the medium and NaCl tolerance of yeast strains was tested. Among the five isolates, SC1 and SCD2 showed maximum ferric oxide reduction and NaCl tolerance. Initially, 5 % of SC1 and SCD2 yeast culture were inoculated in wastewater containing azo dye (100 µg/ml) in a H-type MFC chamber and 250 ml conical flask used as a control. Increased growth of yeast strain in MFC chamber was noted compared to conical flask culture. The data of electricity generation was taken for 15 days and electricity generation was measured using the multimeter. Maximum electricity generation was noted in SC1 (950mV) followed by SCD2 (750mV). In addition, SC1 could degrade azo dye more efficiently than SCD2. Therefore, it may be concluded thatSC1 yeast mediated MFC can be used as a potential technology for electricity generation and degradation of azo dye in wastewater.
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Park, David, and Christian Badr. "DDRE-05. STEAROYL COA DESATURASE IS ESSENTIAL FOR REGULATION OF ENDOPLASMIC RETICULUM HOMEOSTASIS AND TUMOR GROWTH IN GLIOBLASTOMA CANCER STEM CELLS." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i7. http://dx.doi.org/10.1093/noajnl/vdab024.027.
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Abstract INTRODUCTION Emerging evidence suggest that, in addition to glucose, fatty acids can also drive glioma growth. Increased lipid synthesis is one of the metabolic hallmarks of cancer, and indeed, unsaturated fatty acids (UFA) are particularly abundant in glioblastoma. However, the exact role of fatty acids in GBM tumors remains unclear. Blocking fatty acids synthesis can present a new therapy for GBM. METHODS Through targeted inhibitors screening on glioma stem cells (GSCs), we found that they are highly susceptible to Stearoyl CoA Desaturase 1 (SCD1) inhibitors. SCD1 is a key enzyme responsible for the conversion of saturated fatty acids (SFA) to UFA. 1) Through cell-based assays and immunoblot analyses, we tried to understand the role of UFA, SFA and SCD1 in GSCs differentiation and proliferation. We investigated the mechanism between fatty acids and tumor growth through ER stress modulation linked with SCD1 expression. 2) As we found that GSCs are highly susceptible to SCD1 inhibition, we tested CAY, SCD1 inhibitor, in GSCs orthotopic mouse models and assess its effect on tumor growth and overall survival. RESULTS We found that GSCs with extensive self-renewal capacity have an increased dependence on SCD1 activity. Through immunoblot analyses, we demonstrated that SCD1 inhibition exacerbates ER stress through accumulation of SFA and SCD1-mediated UFA synthesis mitigates ER stress. Survival analyses between SCD1 inhibitor-treated group and control group showed significant survival benefit in SCD1-inhibitor-treated group, in both mesenchymal (p=0.008, 35 days vs 18) and proneural (p=0.0002) type glioma cells (n=8/groups). CONCLUSIONS We demonstrate that SCD1, the fatty acid desaturase, is essential for the maintenance of glioblastoma cancer stem cells. SCD1 is activated by ER stress and exerts a cytoprotective function by regulating ER homeostasis, thus favoring survival and tumor growth. Pharmacological targeting of SCD1 exhibits potent therapeutic efficacy in brain tumor mouse models.
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Olichwier, Adam, Volodymyr V. Balatskyi, Marcin Wolosiewicz, James M. Ntambi, and Pawel Dobrzyn. "Interplay between Thyroid Hormones and Stearoyl-CoA Desaturase 1 in the Regulation of Lipid Metabolism in the Heart." International Journal of Molecular Sciences 22, no. 1 (December 24, 2020): 109. http://dx.doi.org/10.3390/ijms22010109.
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Stearoyl-CoA desaturase 1 (SCD1), an enzyme that is involved in the biosynthesis of monounsaturated fatty acids, induces the reprogramming of cardiomyocyte metabolism. Thyroid hormones (THs) activate both lipolysis and lipogenesis. Many genes that are involved in lipid metabolism, including Scd1, are regulated by THs. The present study used SCD1 knockout (SCD1−/−) mice to test the hypothesis that THs are important factors that mediate the anti-steatotic effect of SCD1 downregulation in the heart. SCD1 deficiency decreased plasma levels of thyroid-stimulating hormone and thyroxine and the expression of genes that regulate intracellular TH levels (i.e., Slc16a2 and Dio1-3) in cardiomyocytes. Both hypothyroidism and SCD1 deficiency affected genomic and non-genomic TH pathways in the heart. SCD1 deficiency is known to protect mice from genetic- or diet-induced obesity and decrease lipid content in the heart. Interestingly, hypothyroidism increased body adiposity and triglyceride and diacylglycerol levels in the heart in SCD1−/− mice. The accumulation of triglycerides in cardiomyocytes in SCD1−/− hypothyroid mice was caused by the activation of lipogenesis, which likely exceeded the upregulation of lipolysis and fatty acid oxidation. Lipid accumulation was also observed in the heart in wildtype hypothyroid mice compared with wildtype control mice, but this process was related to a reduction of triglyceride lipolysis and fatty acid oxidation. We also found that simultaneous SCD1 and deiodinase inhibition increased triglyceride content in HL-1 cardiomyocytes, and this process was related to the downregulation of lipolysis. Altogether, the present results suggest that THs are an important part of the mechanism of SCD1 in cardiac lipid utilization and may be involved in the upregulation of energetic metabolism that is associated with SCD1 deficiency.
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Ralston, Jessica C. "Elucidating the roles of stearoyl-CoA desaturase 1 in adipocyte fatty acid metabolism and cellular function." Applied Physiology, Nutrition, and Metabolism 40, no. 12 (December 2015): 1313. http://dx.doi.org/10.1139/apnm-2015-0498.
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Worldwide obesity rates have risen to epidemic proportions, with over 600 million obese individuals across the globe. These individuals are prone to obesity-related health complications, including type 2 diabetes, hypertension, cancer, and cardiovascular disease. Obesity also coincides with the expansion of adipose tissue, which has an important role storing excess calories in the form of triacylglycerol (TAG) within adipocyte lipid droplets. The predominant fatty acids (FAs), comprising adipocyte TAGs, are monounsaturated FAs, which are produced by stearoyl-CoA desaturase 1 (SCD1). Specifically, SCD1 converts saturated FAs palmitate (PA) and stearate (SA) into palmitoleate and oleate, respectively. Interestingly, whole-body SCD1-deficiency is associated with reduced lipogenesis and adiposity. This places SCD1 as a potential target for obesity therapies; however, our understanding of the mechanisms linking SCD1 with changes in adipocyte function remains unclear. This thesis provides important new insights into how SCD1 impacts adipocyte FA metabolism and cellular function. Using a specific SCD1 inhibitor, changes in lipid metabolism, global gene expression, inflammation, cellular stress, and basal insulin signaling were assessed in 3T3-L1 adipocytes. Results demonstrated that SCD1 inhibition caused a reduction in TAGs and phospholipids, which coincided with the downregulation of genes associated with the biosynthesis of these lipid fractions. Cellular diacylglycerols were increased with SCD1 inhibition and insulin signaling was partially impaired. In contrast, markers of cellular stress were unaltered. Furthermore, the FA composition of each lipid fraction was dramatically modified, with SCD1-inhibited adipocytes specifically upregulating the elongation of PA to SA. Stable isotope tracer experiments revealed that this elongation was occurring via elongase 6. Additionally, reduced SCD1 activity in adipocytes exacerbated the effects of exogenous SA on markers of inflammation. Taken together, SCD1 activity has many indirect influences on adipocyte metabolism in addition to its role in FA desaturation. Importantly, SCD1 facilitates the storage of FAs in TAGs and the ability of adipocytes to handle exogenous FAs. SCD1 also prevents saturated FA and DAG accumulation, and preserves insulin signaling in adipocytes. Ultimately this thesis highlights the importance of SCD1 in the maintenance of adipocyte cellular function, and emphasizes the wide-ranging impact of SCD1 on adipocyte FA metabolism.
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Rezamand, Pedram, Jason S. Watts, Katherine M. Yavah, Erin E. Mosley, Liying Ma, Benjamin A. Corl, and Mark A. McGuire. "Relationship between stearoyl-CoA desaturase 1 gene expression, relative protein abundance, and its fatty acid products in bovine tissues." Journal of Dairy Research 81, no. 3 (June 6, 2014): 333–39. http://dx.doi.org/10.1017/s0022029914000181.
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Stearoyl-CoA desaturase 1 (SCD1) greatly contributes to the unsaturated fatty acids present in milk and meat of cattle. The SCD1 enzyme introduces a double bond into certain saturated fatty acyl-CoAs producing monounsaturated fatty acids (MUFA). The SCD1 enzyme also has been shown to be active in the bovine mammary gland converting t11 18 : 1 (vaccenic acid) to c9 t11 conjugated linoleic acid (CLA). The objective of this study was to determine any association between the gene expression of SCD1 and occurrence of its products (c9 14 : 1, c9 16 : 1, c9 18 : 1, and c9 t11 18 : 2) in various bovine tissues. Tissue samples were obtained from lactating Holstein cows (n=28) at slaughter, frozen in liquid nitrogen and stored at −80 °C. Total RNA was extracted and converted to complementary DNA for quantitative real time polymerase chain reaction (PCR) analysis of the SCD1 gene. Extracted lipid was converted to fatty acid methyl esters and analysed by GC. Tissues varied in expression of SCD1 gene with mammary, cardiac, intestinal adipose, and skeletal muscle expressing greater copy number as compared with lung, large intestine, small intestine and liver (371, 369, 328, 286, 257, 145, 73, and 21 copies/ng RNA, respectively). Tissues with high mRNA expression of SCD1 contained greater SCD1 protein whereas detection of SCD1 protein in tissues with low SCD1 mRNA expression was very faint or absent. Across tissues, the desaturase indices for c9 18 : 1 (r=0·24) and sum of SCD products (r=0·20) were positively correlated with SCD1 gene expression (P<0·01 for both). Within each tissue, the relationship between SCD1 gene expression and the desaturase indices varied. No correlation was detected between SCD1 expression and desaturase indices in the liver, large and small intestines, lung, cardiac or skeletal muscles. Positive correlations, however, were detected between SCD1 expression and the desaturase indices in intestinal adipose tissue (P<0·02 for all) except 14 : 1, whereas only c9 18 : 1, c9 t11 18 : 2 and sum of all desaturase indices were positively correlated with SCD1 expression in mammary tissue (P⩽0·03). Overall, the relationship between SCD1 gene expression and occurrence of its products seems to be tissue specific.
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Petroff, Anna B., Rebecca L. Weir, Charles R. Yates, Joseph D. Ng, and Jerome Baudry. "Sequential Dynamics of Stearoyl-CoA Desaturase-1(SCD1)/Ligand Binding and Unbinding Mechanism: A Computational Study." Biomolecules 11, no. 10 (September 30, 2021): 1435. http://dx.doi.org/10.3390/biom11101435.
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Stearoyl-CoA desaturase-1 (SCD1 or delta-9 desaturase, D9D) is a key metabolic protein that modulates cellular inflammation and stress, but overactivity of SCD1 is associated with diseases, including cancer and metabolic syndrome. This transmembrane endoplasmic reticulum protein converts saturated fatty acids into monounsaturated fatty acids, primarily stearoyl-CoA into oleoyl-CoA, which are critical products for energy metabolism and membrane composition. The present computational molecular dynamics study characterizes the molecular dynamics of SCD1 with substrate, product, and as an apoprotein. The modeling of SCD1:fatty acid interactions suggests that: (1) SCD1:CoA moiety interactions open the substrate-binding tunnel, (2) SCD1 stabilizes a substrate conformation favorable for desaturation, and (3) SCD1:product interactions result in an opening of the tunnel, possibly allowing product exit into the surrounding membrane. Together, these results describe a highly dynamic series of SCD1 conformations resulting from the enzyme:cofactor:substrate interplay that inform drug-discovery efforts.
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Berthelot, V., L. Bernard, C. Richard, P. Chavatte-Palmer, and Y. Heyman. "44 MUSCLE FATTY ACID COMPOSITION AND LIPOGENIC GENE EXPRESSION IN ADULT BOVINE CLONES AND CONTROL CATTLE." Reproduction, Fertility and Development 22, no. 1 (2010): 179. http://dx.doi.org/10.1071/rdv22n1ab44.
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Previous evaluation of milk and meat from clone cattle compared with AI control cows indicated that these products were in the normal range of data, but slight differences were observed in their fatty acid (FA) composition and muscle Δ9-desaturase indexes (Heyman et al. 2007 Animal 1, 936-972). It was therefore hypothesized that epigenic modifications induced by the nuclear transfer technology may affect the expression of the 2 genes [stearoyl-coenzyme A desaturase (SCD)-1, SCD5] responsible for Δ9-desaturation in bovines. The aim of the present experiment was to analyze the differences between clones and controls on FA composition and on SCD1 and SCD5 gene expression of the semitendinosus (ST) muscle. Biopsies of ST were taken from 5 clones from 2 different Holstein genotypes and 5 Holstein AI controls at 26 months of age. Each sample was immediately split into 3 aliquots, frozen in liquid nitrogen, and stored at -80°C until analysis. Fatty acid composition was analyzed by gas chromatography after lipid extraction and methylation according to Bas et al. (2005 Meat Sci. 71, 317-326). Total RNA was isolated from 300 mg of muscle tissue and abundance of SCD1 and SCD5 genes transcripts was determined by RT-PCRas described by Bernard et al. (2005 J. Dairy Sci. 88, 1478-1489) and Lengi and Corl (2007 Lipids 42, 499-508). Results are expressed as percentage of total FA for the FA composition and mRNA abundance of SCD1 and SCD5 determined as relative to the abundance of cyclophilin A mRNA. Statistical analyses were performed using the GLM procedure of SAS (SAS Institute, Cary, NC). Single degree of freedom orthogonal contrasts were used to compare effects of cloning (AI controls v. clones) as well as effects of clone genotypes (genotype 1 v. genotype 2). The C14:0, C14:1 cis-9, C16:0, C16:1 cis-9, and C18:0 proportions in ST were not different between clones and controls. However, clones tended to have a lower proportion of C18:1 n - 9 (-3.1% of total FA; P < 0.07) and higher proportions of C18:2 n - 6 (+1.2% of total FA; P < 0.01), C18:3 n - 3 (+0.7% of total FA; P < 0.05) and n - 3 polyunsaturated FA (+1.17% of total FA; P < 0.05) than controls. Ratios of C14 and C16 Δ9-desaturation in ST were not different between clones and controls but a lower C18 Δ9-desaturation ratio for the clones compared with controls was observed (0.76 v. 0.79; P < 0.05). The mRNA abundance of SCD1 was lower in clone compared with control cows (3.8 v. 8.5; P < 0.05), which could be explained by the higher proportion of n - 3 polyunsaturated FA observed in clones because of the negative effects of these polyunsaturated FA on SCD gene expression. The only difference observed between genotypes was for the C18:0 proportion in muscle (P < 0.05). In conclusion, in our set of animals, cloning decreased the ST muscle gene expression of SCD1 but not of SCD5, which is related to a slight decrease in C18 Δ9-desaturation ratio.
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Qin, Xian-Yang, and Soichi Kojima. "Inhibition of Stearoyl-CoA Desaturase-1 Activity Suppressed SREBP Signaling in Colon Cancer Cells and Their Spheroid Growth." Gastrointestinal Disorders 1, no. 1 (January 26, 2019): 191–200. http://dx.doi.org/10.3390/gidisord1010014.
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Unsaturated fatty acids are critical in promoting colon tumorigenesis and its stemness. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipid desaturase associated with colon cancer cell proliferation and metastasis control. This study aims to evaluate the effects of SCD1 inhibition on colon cancer spheroid growth in a three-dimensional cell culture system. An analysis of clinical data showed that increased SCD1 gene expression in colon tumors was negatively correlated with the prognosis. A chemical inhibitor of SCD1, CAY10566, inhibited the growth of colon cancer cells in both monolayer and sphere cultures. In addition, oleic acid administration—a monounsaturated fatty acid generated by the action of SCD1—prevented the suppression of sphere formation by CAY10566. RNA-sequencing data from 382 colon tumor patient samples obtained from the Cancer Genome Atlas database showed that 806 genes were SCD1-associated genes in human colon cancer. Correlation analysis identified the master regulator of lipid homeostasis sterol regulatory element-binding protein 2 (SREBP2) as a prominent transcription factor, whose expression was positively correlated with SCD1 in human colon cancer. SCD1 knockdown using siRNA in colon cancer samples, suppressed SREBP2 gene expression, providing direct evidence that SREBP signaling is under the control of SCD1 in these cells. Pathway analysis in the Ingenuity Pathways Analysis platform showed that SCD1 expression positively correlated with genes involved in multiple pathways, including lipid synthesis and incorporation, cell proliferation, and tissue tumorigenesis. Further network analysis revealed a central role for Myc in the network hierarchy of the SCD1-correlated genes. These findings suggested that SCD1 inhibition would be an effective strategy for suppressing colon cancer spheroid growth, partly through downregulating SREBP-mediated lipid and cholesterol metabolism and Myc signaling.
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Tian, Huibin, Huimin Niu, Jun Luo, Weiwei Yao, Wenchang Gao, Yang Wen, Min Cheng, Anmin Lei, and Jinlian Hua. "Effects of CRISPR/Cas9-mediated stearoyl-Coenzyme A desaturase 1 knockout on mouse embryo development and lipid synthesis." PeerJ 10 (September 14, 2022): e13945. http://dx.doi.org/10.7717/peerj.13945.
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Background Lipid synthesis is an indispensable process during embryo and growth development. Abnormal lipid synthesis metabolism can cause multiple metabolic diseases including obesity and hyperlipidemia. Stearoyl-Coenzyme A desaturase 1 (SCD1) is responsible for catalyzing the synthesis of monounsaturated fatty acids (MUFA) and plays an essential role in lipid metabolism. The aim of our study was to evaluate the effects of SCD1 on embryo development and lipid synthesis in a knockout mice model. Methods We used the CRISPR/Cas9 system together with microinjection for the knockout mouse model generation. Ten-week-old female C57BL/6 mice were used for zygote collection. RNase-free water was injected into mouse zygotes at different cell phases in order to select the optimal time for microinjection. Five sgRNAs were designed and in vitro transcription was performed to obtain sgRNAs and Cas9 mRNA. RNase-free water, NC sgRNA/Cas9 mRNA, and Scd1 sgRNA/Cas9 mRNA were injected into zygotes to observe the morula and blastocyst formation rates. Embryos that were injected with Scd1 sgRNA/Cas9 mRNA and developed to the two-cell stage were used for embryo transfer. Body weight, triacylglycerol (TAG), and cholesterol in Scd1 knockout mice serum were analyzed to determine the effects of SCD1 on lipid metabolism. Results Microinjection performed during the S phase presented with the highest zygote survival rate (P < 0.05). Of the five sgRNAs targeted to Scd1, two sgRNAs with relatively higher gene editing efficiency were used for Scd1 knockout embryos and mice generation. Genome sequence modification was observed at Scd1 exons in embryos, and Scd1 knockout reduced blastocyst formation rates (P < 0.05). Three Scd1 monoallelic knockout mice were obtained. In mice, the protein level of SCD1 decreased (P < 0.05), and the body weight and serum TAG and cholesterol contents were all reduced (P < 0.01).
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Dobrzyn, Agnieszka, Pawel Dobrzyn, Seong-Ho Lee, Makoto Miyazaki, Paul Cohen, Esra Asilmaz, D. Grahame Hardie, Jeffrey M. Friedman, and James M. Ntambi. "Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing β-oxidation in skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 288, no. 3 (March 2005): E599—E607. http://dx.doi.org/10.1152/ajpendo.00439.2004.
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Stearoyl-CoA desaturase (SCD) has recently been shown to be a critical control point of lipid partitioning and body weight regulation. Lack of SCD1 function significantly increases insulin sensitivity in skeletal muscles and corrects the hypometabolic phenotype of leptin-deficient ob/ ob mice, indicating the direct antilipotoxic action of SCD1 deficiency. The mechanism underlying the metabolic effects of SCD1 mutation is currently unknown. Here we show that SCD1 deficiency reduced the total ceramide content in oxidative skeletal muscles (soleus and red gastrocnemius) by ∼40%. The mRNA levels and activity of serine palmitoyltransferase (SPT), a key enzyme in ceramide synthesis, as well as the incorporation of [14C]palmitate into ceramide were decreased by ∼50% in red muscles of SCD1 −/− mice. The content of fatty acyl-CoAs, which contribute to de novo ceramide synthesis, was also reduced. The activity and mRNA levels of carnitine palmitoyltransferase I (CPT I) and the rate of β-oxidation were increased in oxidative muscles of SCD1 −/− mice. Furthermore, SCD1 deficiency increased phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK activation may be partially responsible for the increased fatty acid oxidation and decreased ceramide synthesis in red muscles of SCD1 −/− mice. SCD1 deficiency also reduced SPT activity and ceramide content and increased AMPK phosphorylation and CPT I activity in muscles of ob/ ob mice. Taken together, these results indicate that SCD1 deficiency reduces ceramide synthesis by decreasing SPT expression and increasing the rate of β-oxidation in oxidative muscles.
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Mohammadzadeh, Fatemeh, Vahid Hosseini, Alireza Alihemmati, Maghsod Shaaker, Gholamali Mosayyebi, Masoud Darabi, and Amir Mehdizadeh. "The Role of Stearoyl-coenzyme A Desaturase 1 in Liver Development, Function, and Pathogenesis." Journal of Renal and Hepatic Disorders 3, no. 1 (February 6, 2019): 15–22. http://dx.doi.org/10.15586/jrenhep.2019.49.
Full textAbstract:
Stearoyl-coenzyme A desaturase 1 (SCD1) is a microsomal enzyme that controls fatty acid metabolism and is highly expressed in hepatocytes. SCD1 may play a key role in liver development and hepatic lipid homeostasis through promoting monounsaturated protein acylation and converting lipotoxic saturated fatty acids into monounsaturated fatty acids. Imbalanced activity of SCD1 has been implicated in fatty liver induction, inflammation and stress. In this review, the role of SCD1 in hepatic development, function and pathogenesis is discussed. Additionally, emerging novel therapeutic agents targeting SCD1 for the treatment of liver disorders are presented.
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Dobosz, Aneta M., Justyna Janikiewicz, Anna M. Borkowska, Anna Dziewulska, Ewelina Lipiec, Pawel Dobrzyn, Wojciech M. Kwiatek, and Agnieszka Dobrzyn. "Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells." International Journal of Molecular Sciences 21, no. 18 (September 18, 2020): 6844. http://dx.doi.org/10.3390/ijms21186844.
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Metabolic stress, such as lipotoxicity, affects the DNA methylation profile in pancreatic β-cells and thus contributes to β-cell failure and the progression of type 2 diabetes (T2D). Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that is involved in monounsaturated fatty acid synthesis, which protects pancreatic β-cells against lipotoxicity. The present study found that SCD1 is also required for the establishment and maintenance of DNA methylation patterns in β-cells. We showed that SCD1 inhibition/deficiency caused DNA hypomethylation and changed the methyl group distribution within chromosomes in β-cells. Lower levels of DNA methylation in SCD1-deficient β-cells were followed by lower levels of DNA methyltransferase 1 (DNMT1). We also found that the downregulation of SCD1 in pancreatic β-cells led to the activation of adenosine monophosphate-activated protein kinase (AMPK) and an increase in the activity of the NAD-dependent deacetylase sirtuin-1 (SIRT1). Furthermore, the physical association between DNMT1 and SIRT1 stimulated the deacetylation of DNMT1 under conditions of SCD1 inhibition/downregulation, suggesting a mechanism by which SCD1 exerts control over DNMT1. We also found that SCD1-deficient β-cells that were treated with compound c, an inhibitor of AMPK, were characterized by higher levels of both global DNA methylation and DNMT1 protein expression compared with untreated cells. Therefore, we found that activation of the AMPK/SIRT1 signaling pathway mediates the effect of SCD1 inhibition/deficiency on DNA methylation status in pancreatic β-cells. Altogether, these findings suggest that SCD1 is a gatekeeper that protects β-cells against the lipid-derived loss of DNA methylation and provide mechanistic insights into the mechanism by which SCD1 regulates DNA methylation patterns in β-cells and T2D-relevant tissues.
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Zhang, Haojian, and Shaoguang Li. "The Scd1 Gene Functions as a Tumor Suppressor In Leukemia Stem Cells." Blood 116, no. 21 (November 19, 2010): 201. http://dx.doi.org/10.1182/blood.v116.21.201.201.
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Abstract Abstract 201 We have previously shown that the arachidonate 5-lipoxygenase gene (Alox5) functions as a critical regulator of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML) in mice. The Alox5 pathway appears to represent a major molecular network in LSCs. Taking advantage of our DNA microarray analysis for the identification of critical genes regulated by BCR-ABL in LSCs, we identified a small group of candidate genes that likely play tumor suppressor roles in these stem cells, and among them, a gene called stearoyl-CoA desaturase 1 (Scd1), an endoplasmic reticulum enzyme catalyzing the biosynthesis of monounsaturated fatty acids from saturated fatty acids, was shown to have a strong inhibitory effect on survival of LSCs in CML mice. BCR-ABL transduced bone marrow cells from Scd1-/- mice induced CML much faster than BCR-ABL transduced wild type bone marrow cells, and overexpression of Scd1 dramatically delayed CML development. Therefore, we further investigated whether Scd1 suppresses LSCs. FACS analysis showed that the percentages and total numbers of LSCs (GFP+ Lin−c-Kit+Sca-1+) and long-term (GFP+ Lin−c-Kit+Sca-1+ CD34−) or short-term (GFP+ Lin−c-Kit+Sca-1+ CD34+) LSCs in bone marrow of recipients of BCR-ABL transduced Scd1-/- donor bone marrow cells were significantly higher than those in bone marrow of recipients of BCR-ABL transduced wild type donor bone marrow cells, suggesting that Scd1 suppresses LSCs. Next we did a competitive repopulation assay to examine the function of LSCs. LSCs were sorted by FACS from bone marrow of mice with primary CML induced by transplanting BCR-ABL-transduced Scd1-/- (CD45.2) or wild type (CD45.1) bone marrow cells. The sorted CD45.2 and CD45.1 LSCs were mixed in a 1:1 ratio, followed by transplantation into lethally irradiated recipient mice to induce secondary CML. At 8 weeks after transplantation, only less than 10% of GFP+Gr-1+ cells were CD45.1 leukemia cells derived from wild type mice, whereas more than 75%-80% of GFP+Gr-1+ cells in peripheral blood of the mice were CD45.2 leukemia cells derived from Scd1-/- mice. To determine how Scd1 deficiency affects the maintenance of LSCs, we examined the cell cycle and apoptosis of LSCs. We found the percentages of apoptotic LSCs (Annexin V+ cells) were significantly decreased in bone marrow and spleens from Scd1-/- CML mice compared to the wild type group; however, we did not observe significant differences in the cell cycle status of LSCs from bone marrow and spleen, indicating that Scd1 regulates apoptosis but not cell cycle of LSCs. PPARγ agonist rosiglitazone can increase Scd1 expression, and our real time PCR data showed that rosiglitazone significantly induced Scd1 expression in bone marrow cells from CML mice. Therefore, we used PPARγ agonist rosiglitazone to treat these cells, and observed that rosiglitazone treatment dramatically decreased LSCs and that loss of Scd1 partially rescued the effect of PPARγ agonist on LSCs. Further, we investigated the molecular mechanisms that may contribute to the acceleration of CML development resulting from Scd1 deficiency. The decreased apoptosis in LSCs from Scd1-/- CML mice led us to focus on apoptosis-related genes. Real time PCR analysis showed a significant decrease of p53 in Scd1-/- immature leukemia cells as compared with that in wild type immature leukemia cells; however, loss of Scd1 resulted in dramatically and modest increased expression of Bcl-2 and Mcl-1 respectively in immature leukemia cells. We also found that the tumor suppressor gene Pten was significantly downregulated in Scd1-/- LSCs. Together, our results demonstrate a novel tumor suppressor function of Scd1 in LSCs, and provide a rationale for suppressing LSCs by enhancing Scd1 expression. Disclosures: No relevant conflicts of interest to declare.
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Dobrzyn, Pawel, Harini Sampath, Agnieszka Dobrzyn, Makoto Miyazaki, and James M. Ntambi. "Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart." American Journal of Physiology-Endocrinology and Metabolism 294, no. 2 (February 2008): E357—E364. http://dx.doi.org/10.1152/ajpendo.00471.2007.
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Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids (FA). SCD1 deficiency activates metabolic pathways that promote FA β-oxidation and decrease lipogenesis in liver. In the present study, we show that FA transport and oxidation are decreased, whereas glucose uptake and oxidation are increased in the heart of SCD1−/− mice. Protein levels of FA transport proteins such as FA translocase/CD36 and FA transport protein as well as activity of carnitine palmitoyltransferase 1, the rate-limiting enzyme for mitochondrial fat oxidation, were significantly lower in the heart of SCD1−/− mice compared with SCD1+/+ mice. Consequently, the rate of palmitoyl-CoA oxidation was decreased significantly in the heart of SCD1−/− mice. mRNA levels of peroxisome proliferator-activated receptor-α, a key transcription factor controlling genes of FA oxidation, were significantly reduced in SCD1−/− mice. Phosphorylation of insulin receptor substrate-1 (IRS-1) and the association of αp85 subunit of phosphatidylinositol 3-kinase with IRS-1 were significantly higher under both basal and insulin-stimulated conditions in SCD1−/− hearts. This increased insulin sensitivity translated to a 1.8-fold greater 2-deoxyglucose uptake and 2-fold higher rate of glucose oxidation in the myocardium compared with SCD1+/+ counterparts. The results suggest that SCD1 deficiency causes a shift in cardiac substrate utilization from FA to glucose by upregulating insulin signaling, decreasing FA availability, and reducing expression of FA oxidation genes in the heart. This increase in cardiac insulin sensitivity and glucose utilization due to SCD1 deficiency could prove therapeutic in pathological conditions such as obesity that are characterized by skewed cardiac substrate utilization.
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Ropka-Molik, K., J. Knapik, M. Pieszka, and T. Szmatoła. "The expression of the SCD1 gene and its correlation with fattening and carcass traits in sheep." Archives Animal Breeding 59, no. 1 (January 25, 2016): 37–43. http://dx.doi.org/10.5194/aab-59-37-2016.
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Abstract. Stearoyl-CoA desaturase 1 (SCD1) is a critical enzyme that catalyzes the synthesis of monounsaturated fatty acids and is involved in several signaling pathways related to lipid metabolism. The objective of the present study was to estimate the expression of the SCD1 gene in three different ovine tissues strongly associated with lipid homeostasis. The SCD1 gene expression measurement was performed on three tissues (liver, subcutaneous fat, perirenal fat) originated from 15 old-type Polish Merino sheep. The SCD1 transcript abundance was evaluated based on the two most stable endogenous controls (RPS2 – ribosomal protein S2; ATP5G2 – H(+)-transporting ATP synthase). The highest expression of the SCD1 gene was observed in ovine subcutaneous fat compared to perirenal fat and liver. Furthermore, the present research indicated the significant correlation between ovine SCD1 transcript abundance and several important production traits. The expression of the SCD1 gene in liver and perirenal fat highly positively correlated with the feed : gain ratio, test of daily gain and age of the animals at slaughter. Moreover, in both tissues, the SCD1mRNA level positively correlated with weight and content of perirenal fat and subcutaneous fat (R = 0.64, 0.8, 0.6, respectively) and negatively with assessment of external fat content with the use of the EUROP scale (R = −0.64). The SCD1 expression in subcutaneous fat also corresponds with back fat of blade chop and thickness of longissimus dorsi muscles evaluated using USG (ultrasonography) (R = −0.6 and 0.62, respectively). The significant correlation between SCD1 transcript abundance and fattening and slaughtering traits indicate the ability to improve important production traits in sheep via modification of expression of the SCD1 gene.
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Zhao, Xiaoyang, Min Wang, Jingjing Liu, and Xiong Su. "Stearoyl CoA Desaturase 1 and Inositol-Requiring Protein 1α Determine the Efficiency of Oleic Acid in Alleviating Silica Nanoparticle-Induced Insulin Resistance." Journal of Biomedical Nanotechnology 17, no. 7 (July 1, 2021): 1349–63. http://dx.doi.org/10.1166/jbn.2021.3109.
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Despite the widespread use of silica nanoparticles (SiNPs), their metabolic impact and mechanisms of action have not been well studied. Exposure to SiNPs induces insulin resistance (IR) in hepatocytes by endoplasmic reticulum (ER) stress via inositol-requiring protein 1α (IRE1α) activation of c-Jun N-terminal kinases (JNK). It has been well established that stearoyl CoA desaturase (SCD1) and its major product oleic acid elicited beneficial effects in restoring ER homeostasis. However, the potential coordination of SCD1 and IRE1α in determining SiNP regulation of insulin signaling is unclear. Herein, we investigated the effects of SCD1 and oleic acid on IR induced by SiNPs or thapsigargin in hepatocytes. SCD1 overexpression or oleic acid efficiently reversed SiNP-induced ER stress and IR, whereas the effects of thapsigargin treatment could not be restored. Thapsigargin diminished SCD1 protein levels, leading to the accumulation of IRE1α and sustained activation of the IRE1α/JNK pathway. Moreover, knockdown of activating transcription factor 4 (ATF4) upstream of SCD1 suppressed SiNP-induced SCD1 expression, rescued the activated IRE1α, and inhibited insulin signaling but was not able to restore the effects of thapsigargin. Collectively, downregulation of SCD1 and excess accumulation of IRE1α protein prevented the beneficial effects of exogenous oleic acid on IR induced by ER stress. Our results provide valuable mechanistic insights into the synergic regulation of IR by SiNPs and ER stress and suggest a combinational strategy to restore ER homeostasis by targeting SCD1 and IRE1α proteins, as well as supplementation of unsaturated fatty acids.
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Levitsky, A., V. Velichko, I. Selivanskaya, and A. Lapinskaya. "Effect of dietary fats on endogenous oleic acid biosynthesis in rat liver." Journal of Education, Health and Sport 12, no. 2 (February 28, 2022): 262–73. http://dx.doi.org/10.12775/jehs.2022.12.02.028.
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Aim: Determine the effect of dietary fats with different fatty acid composition on the biosynthesis of oleic acid and its metabolic precursors in the liver .
Methods: High linoleic sunflower oil (HLSO), high oleic sunflower oil (HOSO) and palm oil (PO) were used. Rats were fed a semi-synthetic fat-free diet (FFD) and fat diets containing 5 % of the above oils (instead of starch) for 30 days. Liver lipids were divided into 3 fractions: neutral lipids (NL), phospholipids (PL) and free fatty acids (FFA). The fatty acid composition of the fractions was determined by gas chromatography. The “activity” of fatty acid synthase was determined from the total content of the products of this reaction (C16:0 and C16:1). The “activity” of palmitic acid elongase was determined by the ratio С18:0/С16:0, as well as by the formula (С18:0+С18:1)/(С16:0–С16:1). The “activity” of stearic acid desaturase (SCD1) was determined by the ratio C16:1/C16:0 (SCD16) and by the ratio C18:1/C18:0 (SCD18).
Results: In rats treated with fat diets, the content of palmitic and oleic acids is reduced only in the NL fraction, and to the greatest extent when consuming the diet with HLSO. The “activity” of palmitic acid elongase increases significantly with the consumption of a diet with HLSO. SCD16 desaturase “activity” decreases with fat diet, while SCD18 desaturase “activity” increases. The level of SCD18 is significantly higher than the level of SCD16. Consumption of HLSO reduces the content of ω-3 PUFA in rat liver lipids, while the intake of HOSO increases it.
Conclusions: HLSO diet reduces the endogenous biosynthesis of oleic and palmitic acids, as determined by the analysis of the rat liver NL fraction. A fat diet reduces SCD16 “activity” but increases SCD18 “activity”, especially when fed a diet with HOSO. The diet with HLSO reduces the content of ω-3 PUFA in liver lipids.
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Levitsky, A., V. Velichko, I. Selivanskaya, and A. Lapinskaya. "Effect of dietary fats on endogenous oleic acid biosynthesis in rat liver." Journal of Education, Health and Sport 12, no. 2 (February 28, 2022): 262–73. http://dx.doi.org/10.12775/jehs.2022.12.02.028.
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Aim: Determine the effect of dietary fats with different fatty acid composition on the biosynthesis of oleic acid and its metabolic precursors in the liver .
Methods: High linoleic sunflower oil (HLSO), high oleic sunflower oil (HOSO) and palm oil (PO) were used. Rats were fed a semi-synthetic fat-free diet (FFD) and fat diets containing 5 % of the above oils (instead of starch) for 30 days. Liver lipids were divided into 3 fractions: neutral lipids (NL), phospholipids (PL) and free fatty acids (FFA). The fatty acid composition of the fractions was determined by gas chromatography. The “activity” of fatty acid synthase was determined from the total content of the products of this reaction (C16:0 and C16:1). The “activity” of palmitic acid elongase was determined by the ratio С18:0/С16:0, as well as by the formula (С18:0+С18:1)/(С16:0–С16:1). The “activity” of stearic acid desaturase (SCD1) was determined by the ratio C16:1/C16:0 (SCD16) and by the ratio C18:1/C18:0 (SCD18).
Results: In rats treated with fat diets, the content of palmitic and oleic acids is reduced only in the NL fraction, and to the greatest extent when consuming the diet with HLSO. The “activity” of palmitic acid elongase increases significantly with the consumption of a diet with HLSO. SCD16 desaturase “activity” decreases with fat diet, while SCD18 desaturase “activity” increases. The level of SCD18 is significantly higher than the level of SCD16. Consumption of HLSO reduces the content of ω-3 PUFA in rat liver lipids, while the intake of HOSO increases it.
Conclusions: HLSO diet reduces the endogenous biosynthesis of oleic and palmitic acids, as determined by the analysis of the rat liver NL fraction. A fat diet reduces SCD16 “activity” but increases SCD18 “activity”, especially when fed a diet with HOSO. The diet with HLSO reduces the content of ω-3 PUFA in liver lipids.
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Yamasaki, Tomohiro, Lumin Zhang, Tyrone Dowdy, Adrian Lita, Mark Gilbert, and Mioara Larion. "TAMI-37. STEAROYL-COA DESATURASE 1 IS ESSENTIAL FOR THE GROWTH OF IDH MUTANT GLIOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi206. http://dx.doi.org/10.1093/neuonc/noab196.821.
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Abstract BACKGROUND Increased de novo lipogenesis is a hallmark of cancer metabolism. In this study, we interrogated the role of de novo lipogenesis in IDH1 mutated glioma’s growth and identified the key enzyme, Stearoyl-CoA desaturase 1 (SCD1) that provides this growth advantage. MATERIALS ANDMETHODS We prepared genetically engineered glioma cell lines (U251 wild-type: U251WT and U251 IDHR132H mutant: U251RH) and normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH). Lipid metabolic analysis was conducted by using LC-MS and Raman imaging microscopy. SCD1 expression was investigated by The Cancer Genome Atlas (TCGA) data analysis and Western-blotting method. Knock-out of SCD1 was conducted by using CRISPR/Cas9 and shRNA. RESULTS Previously, we showed that IDH1 mut glioma cells have increased monounsaturated fatty acids (MUFAs). TCGA data revealed IDH mut glioma shows significantly higher SCD1 mRNA expression than wild-type glioma. Our model systems of IDH1 mut (U251RH, NHARH) showed increased expression of this enzyme compared with their wild-type counterpart. Moreover, addition of D-2HG to U251WT increased SCD1 expression. Herein, we showed that inhibition of SCD1 with CAY10566 decreased relative cell number and sphere forming capacity in a dose-dependent manner. Furthermore, addition of MUFAs were able to rescue the SCD1 inhibitor induced-cell death and sphere forming capacity. Knock out of SCD1 revealed decreased cell proliferation and sphere forming ability. Decreasing lipid content from the media did not alter the growth of these cells, suggesting that glioma cells rely on de novo lipid synthesis rather than scavenging them from the microenvironment. CONCLUSION Overexpression of IDH mutant gene altered lipid composition in U251 cells to enrich MUFA levels and we confirmed that D-2HG caused SCD1 upregulation in U251WT. We demonstrated the glioma cell growth requires SCD1 expression and the results of the present study may provide novel insights into the role of SCD1 in IDH mut gliomas growth.
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Peter, Andreas, Alexander Cegan, Silvia Wagner, Rainer Lehmann, Norbert Stefan, Alfred Königsrainer, Ingmar Königsrainer, Hans-Ulrich Häring, and Erwin Schleicher. "Hepatic Lipid Composition and Stearoyl-Coenzyme A Desaturase 1 mRNA Expression Can Be Estimated from Plasma VLDL Fatty Acid Ratios." Clinical Chemistry 55, no. 12 (December 1, 2009): 2113–20. http://dx.doi.org/10.1373/clinchem.2009.127274.
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Abstract Background: Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the limiting step of monounsaturated fatty acid synthesis in humans and is an important player in triglyceride generation. SCD1 has been repeatedly implicated in the pathogenesis of metabolic and inflammatory diseases. Therefore it is of great importance to determine SCD1 activity in human samples. In this study we aimed to evaluate a hepatic SCD1 activity index derived from plasma VLDL triglyceride composition as a tool to estimate hepatic SCD1 expression in humans. Additionally, we further evaluated commonly used fatty acid ratios [elongase, de novo lipogenesis, and Δ5 and Δ6 desaturase] in plasma VLDL and hepatic lipid fractions. Design and methods: Liver biopsies and plasma samples were simultaneously collected from 15 individuals. Plasma VLDL was obtained by ultracentrifugation. Hepatic and plasma VLDL lipids were fractionated by thin-layer chromatography, and the fatty acid composition of each fraction was analyzed by gas chromatography. Hepatic SCD1 expression was determined by real-time PCR. Results: Hepatic SCD1 mRNA expression was associated with the product/precursor ratios (16:1/16:0 and 18:1/18:0) of hepatic lipid fractions. The 16:1/16:0 ratio in hepatic and VLDL triglycerides as well as the 18:1/18:0 ratio in plasma VLDL were closely associated with hepatic SCD1 expression. The hepatic de novo lipogenesis index from triglycerides was associated with expression of lipogenic genes [fatty acid synthase (FASN), acetyl-Coenzyme A carboxylase alpha (ACACA), and sterol regulatory element binding transcription factor 1 (SREBP-1)] and is closely reflected by the de novo lipogenesis index in VLDL triglycerides. Conclusion: We demonstrated for the first time that hepatic SCD1 expression can be estimated noninvasively from routine blood samples by measuring the SCD1 activity index in fasting plasma VLDL.
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Peng, Liying, Ge Bai, Chunzheng Wang, Jianan Dong, Yongjun Liu, Zhe Sun, Yuguo Zhen, et al. "Proteomics Insights into the Gene Network of cis9, trans11-Conjugated Linoleic Acid Biosynthesis in Bovine Mammary Gland Epithelial Cells." Animals 12, no. 13 (July 2, 2022): 1718. http://dx.doi.org/10.3390/ani12131718.
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The objective of the study was to elucidate the stearoyl-coenzyme A desaturase (SCD1)-dependent gene network of c9, t11-CLA biosynthesis in MAC-T cells from an energy metabolism perspective. The cells were divided into the CAY group (firstly incubated with CAY10566, a chemical inhibitor of SCD1, then incubated with trans-11-octadecenoic acid, (TVA)), the TVA group (only TVA), and the control group (without CAY, TVA). The c9, t11-CLA, and TVA contents were determined by gas chromatography. The mRNA levels of SCD1 and candidate genes were analyzed via real-time PCR. Tandem mass tag (TMT)-based quantitative proteomics, bioinformatic analysis, parallel reaction monitoring (PRM), and small RNA interference were used to explore genes involved in the SCD1-dependent c9, t11-CLA biosynthesis. The results showed that the SCD1 deficiency led by CAY10566 blocked the biosynthesis of c9, t11-CLA. In total, 60 SCD1-related proteins mainly involved in energy metabolism pathways were primarily screened by TMT-based quantitative proteomics analysis. Moreover, 17 proteins were validated using PRM analysis. Then, 11 genes were verified to have negative relationships with SCD1 after the small RNA interference analysis. Based on the above results, we concluded that genes involved in energy metabolism pathways have an impact on the SCD1-dependent molecular mechanism of c9, t11-CLA biosynthesis.
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Dragos, Steven M., Karl F. Bergeron, Frédérik Desmarais, Katherine Suitor, David C. Wright, Catherine Mounier, and David M. Mutch. "Reduced SCD1 activity alters markers of fatty acid reesterification, glyceroneogenesis, and lipolysis in murine white adipose tissue and 3T3-L1 adipocytes." American Journal of Physiology-Cell Physiology 313, no. 3 (September 1, 2017): C295—C304. http://dx.doi.org/10.1152/ajpcell.00097.2017.
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White adipose tissue (WAT) has a critical role in lipid handling. Previous work demonstrated that SCD1 is an important regulator of WAT fatty acid (FA) composition; however, its influence on the various interconnected pathways influencing WAT lipid handling remains unclear. Our objective was to investigate the role of SCD1 on WAT lipid handling using Scd1 knockout (KO) mice and SCD1-inhibited 3T3-L1 adipocytes by measuring gene, protein, and metabolite markers related to FA reesterification, glyceroneogenesis, and lipolysis. Triacylglycerol (TAG) content was higher in inguinal WAT (iWAT) from KO mice compared with wild-type, but significantly lower in epididymal WAT (eWAT). The SCD1 desaturation index was decreased in both WAT depots in KO mice. FA reesterification, as measured with a NEFA:glycerol ratio, was reduced in both WAT depots in KO mice, as well as SCD1-inhibited 3T3-L1 adipocytes. Pck1, Atgl, and Hsl gene expression was reduced in both WAT depots of KO mice, while Pck2 and Pdk4 gene expression showed depot-specific regulation. Pck1, Atgl, and Hsl gene expression was reduced, and phosphoenolpyruvate carboxykinase protein content was ablated, in SCD1-inhibited adipocytes. Our data provide evidence that SCD1 has a broad impact on WAT lipid handling by altering TAG composition in a depot-specific manner, reducing FA reesterification, and regulating markers of lipolysis and glyceroneogenesis.
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Zou, Ying, Yi-Na Wang, Hong Ma, Zhi-Hui He, Yan Tang, Liang Guo, Yang Liu, Meng Ding, Shu-Wen Qian, and Qi-Qun Tang. "SCD1 promotes lipid mobilization in subcutaneous white adipose tissue." Journal of Lipid Research 61, no. 12 (September 25, 2020): 1589–604. http://dx.doi.org/10.1194/jlr.ra120000869.
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Beiging of white adipose tissue (WAT) has beneficial effects on metabolism. Although it is known that beige adipocytes are active in lipid catabolism and thermogenesis, how they are regulated deserves more explorations. In this study, we demonstrate that stearoyl-CoA desaturase 1 (SCD1) in subcutaneous WAT (scWAT) responded to cold stimulation and was able to promote mobilization of triacylglycerol [TAG (triglyceride)]. In vitro studies showed that SCD1 promoted lipolysis in C3H10T1/2 white adipocytes. The lipolytic effect was contributed by one of SCD1’s products, oleic acid (OA). OA upregulated adipose TAG lipase and hormone-sensitive lipase expression. When SCD1 was overexpressed in the scWAT of mice, lipolysis was enhanced, and oxygen consumption and heat generation were increased. These effects were also demonstrated by the SCD1 knockdown experiments in mice. In conclusion, our study suggests that SCD1, known as an enzyme for lipid synthesis, plays a role in upregulating lipid mobilization through its desaturation product, OA.
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Stamatikos, Alexis D., and Chad M. Paton. "Role of stearoyl-CoA desaturase-1 in skeletal muscle function and metabolism." American Journal of Physiology-Endocrinology and Metabolism 305, no. 7 (October 1, 2013): E767—E775. http://dx.doi.org/10.1152/ajpendo.00268.2013.
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Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids (SFA) into monounsaturated fatty acids and is necessary for proper liver, adipose tissue, and skeletal muscle lipid metabolism. While there is a wealth of information regarding SCD1 expression in the liver, research on its effect in skeletal muscle is scarce. Furthermore, the majority of information about its role is derived from global knockout mice, which are known to be hypermetabolic and fail to accumulate SCD1's substrate, SFA. We now know that SCD1 expression is important in regulating lipid bilayer fluidity, increasing triglyceride formation, and enabling lipogenesis and may protect against SFA-induced lipotoxicity. Exercise has been shown to increase SCD1 expression, which may contribute to an increase in intramyocellular triglyceride at the expense of free fatty acids and diacylglycerol. This review is intended to define the role of SCD1 in skeletal muscle and discuss the potential benefits of its activity in the context of lipid metabolism, insulin sensitivity, exercise training, and obesity.
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Zhang, Yahua, Xiaoyan Zhang, Lihong Chen, Jing Wu, Dongming Su, Wendell J. Lu, Mei-Tsuey Hwang, et al. "Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule." American Journal of Physiology-Renal Physiology 290, no. 5 (May 2006): F1065—F1073. http://dx.doi.org/10.1152/ajprenal.00131.2005.
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Liver X receptors (LXRs), including LXRα and LXRβ, are intracellular sterol sensors that regulate expression of genes controlling fatty acid and cholesterol absorption, excretion, catabolism, and cellular efflux. Because the kidney plays an important role in lipid metabolism and dyslipidemia accelerates renal damage, we investigated the effect of TO-901317, an LXR agonist, on the gene expression profile in mouse kidney. Treatment of C57 Bl/6 mice with TO-901317 (3 mg·kg−1·day−1) for 3 days resulted in 51 transcripts that were significantly regulated in the kidney. Among them, the stearoyl-CoA desaturase-1 (SCD1) was upregulated most dramatically. Northern blot analysis revealed that SCD1 mRNA levels were markedly higher than that in control kidneys. Enhanced SCD1 expression by TO-901317 also resulted in increased fatty acid desaturation in the kidney. In control mice, constitutive renal SCD1 expression was low; however, TO-901317 treatment markedly increased SCD1 expression in the outer stripe of the outer medulla as assessed by both in situ hybridization and immunostain. Double-labeling studies further indicated that SCD1 mRNA was selectively expressed in proximal straight tubules negative for aquaporin-2 and Tamm-Horsfall protein. In vitro studies in cultured murine proximal tubule cells further demonstrated that LXR activation enhanced SCD1 transcription via increased sterol regulatory element binding protein-1. Taken together, these data suggest LXR activation of SCD1 expression may play an important role in regulating lipid metabolism and cell function in renal proximal straight tubules.
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Yu, Yeongji, Hyejin Kim, SeokGyeong Choi, JinSuh Yu, Joo Yeon Lee, Hani Lee, Sukjoon Yoon, and Woo-Young Kim. "Targeting a Lipid Desaturation Enzyme, SCD1, Selectively Eliminates Colon Cancer Stem Cells through the Suppression of Wnt and NOTCH Signaling." Cells 10, no. 1 (January 8, 2021): 106. http://dx.doi.org/10.3390/cells10010106.
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The elimination of the cancer stem cell (CSC) population may be required to achieve better outcomes of cancer therapy. We evaluated stearoyl-CoA desaturase 1 (SCD1) as a novel target for CSC-selective elimination in colon cancer. CSCs expressed more SCD1 than bulk cultured cells (BCCs), and blocking SCD1 expression or function revealed an essential role for SCD1 in the survival of CSCs, but not BCCs. The CSC potential selectively decreased after treatment with the SCD1 inhibitor in vitro and in vivo. The CSC-selective suppression was mediated through the induction of apoptosis. The mechanism leading to selective CSC death was investigated by performing a quantitative RT-PCR analysis of 14 CSC-specific signaling and marker genes after 24 and 48 h of treatment with two concentrations of an inhibitor. The decrease in the expression of Notch1 and AXIN2 preceded changes in the expression of all other genes, at 24 h of treatment in a dose-dependent manner, followed by the downregulation of most Wnt- and NOTCH-signaling genes. Collectively, we showed that not only Wnt but also NOTCH signaling is a primary target of suppression by SCD1 inhibition in CSCs, suggesting the possibility of targeting SCD1 against colon cancer in clinical settings.
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Lee, Dong-Kyung, Kwang-Hwan Choi, Jae Yeon Hwang, Jong-Nam Oh, Seung-Hun Kim, and Chang-Kyu Lee. "Stearoyl-coenzyme A desaturase 1 is required for lipid droplet formation in pig embryo." Reproduction 157, no. 3 (March 2019): 235–43. http://dx.doi.org/10.1530/rep-18-0556.
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Lipid droplets (LD) provide a source of energy, and their importance during embryogenesis has been increasingly recognized. In particular, pig embryos have larger amounts of intercellular lipid bilayers than other mammalian species, suggesting that porcine embryos are more dependent on lipid metabolic pathways. The objective of the present study was to detect the effect of stearoyl-coenzyme A desaturase 1 (SCD1) on LD formation and to associate these effects with the mRNA abundance of LD formation-related genes (SREBP, ARF1, COPG2, PLD1 and ERK2) in in vitro-produced porcine embryos. To determine the effect of SCD1 on LD formation and related genes, we examined the effects of SCD1 inhibition using CAY10566 (an SCD1 inhibitor, 50 μM) on parthenogenetic embryos. SCD1 inhibition downregulated the mRNA levels of LD formation-related genes and embryo development. Our results revealed that SCD1 functions in the regulation of LD formation via phospholipid formation and embryo development. In addition, we treated parthenogenetic embryos with oleic acid (100 μM), which led to a significant increase in the blastocyst formation rate, LD size and number compared to controls. Remarkably, the adverse effects of the SCD1 inhibitor could be counteracted by oleic acid. These data suggest that porcine embryos can use exogenous oleic acid as a metabolic energy source.
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Yu, Yeongji, Hyejin Kim, SeokGyeong Choi, JinSuh Yu, Joo Yeon Lee, Hani Lee, Sukjoon Yoon, and Woo-Young Kim. "Targeting a Lipid Desaturation Enzyme, SCD1, Selectively Eliminates Colon Cancer Stem Cells through the Suppression of Wnt and NOTCH Signaling." Cells 10, no. 1 (January 8, 2021): 106. http://dx.doi.org/10.3390/cells10010106.
Full textAbstract:
The elimination of the cancer stem cell (CSC) population may be required to achieve better outcomes of cancer therapy. We evaluated stearoyl-CoA desaturase 1 (SCD1) as a novel target for CSC-selective elimination in colon cancer. CSCs expressed more SCD1 than bulk cultured cells (BCCs), and blocking SCD1 expression or function revealed an essential role for SCD1 in the survival of CSCs, but not BCCs. The CSC potential selectively decreased after treatment with the SCD1 inhibitor in vitro and in vivo. The CSC-selective suppression was mediated through the induction of apoptosis. The mechanism leading to selective CSC death was investigated by performing a quantitative RT-PCR analysis of 14 CSC-specific signaling and marker genes after 24 and 48 h of treatment with two concentrations of an inhibitor. The decrease in the expression of Notch1 and AXIN2 preceded changes in the expression of all other genes, at 24 h of treatment in a dose-dependent manner, followed by the downregulation of most Wnt- and NOTCH-signaling genes. Collectively, we showed that not only Wnt but also NOTCH signaling is a primary target of suppression by SCD1 inhibition in CSCs, suggesting the possibility of targeting SCD1 against colon cancer in clinical settings.
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Hilmia, N., R. R. Noor, C. Sumantri, R. E. Gurnadi, and R. Priyanto. "Polymorphism of stearoyl-CoA desaturase (SCD1) gene in Indonesian local cattle." Journal of the Indonesian Tropical Animal Agriculture 42, no. 1 (February 28, 2017): 1. http://dx.doi.org/10.14710/jitaa.42.1.1-5.
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Stearoyl-Coa desaturase (SCD1) gene is one of genes that involves in converting saturated fatty acids to unsaturated fatty acids. SNP at exon 5 in SCD1 gene that changes amino acid valine to alanine (V293A) has an influence to meat fatty acid composition. The aim of this research was to analyze SCD1 gene polymorphisms based on SNP V293A at exon 5 of three Indonesian local cattle. The identification of SCD1 gene polymorphisms was done by using 98, 20 and 7 DNA sample from Ciamis, Bali/Banteng, and Ongole Grade (PO) cattle, respectively. PCR_RFLP method with AciI enzim was carried out to identify SNP Val293Ala. Allelic frequencies and heterozygosity value were analyzed by using POPGENE32. The result showed that SCD1 gene at Ciamis local cattle and PO cattle were polymorphic. Their frequencies were 74.5% and 71.4% for T and 25.5% and 28.6% for C, respectively. There were three genotypes on Ciamis local cattle i.e TT, CT and CC with their frequencies were 52%, 44.9% and 3.10%, respectively. There were two genotypes on PO cattle i.e TT and CT with their frequencies were 42.9% and 57.1%, respectively. Meanwhile, SCD1 gene in Bali cattle was monomorphic. Heterozygosity value of SCD1 gene in Ciamis and PO cattle were 0.38 and 0.44, respectively. Their heterozigosities were categorized as medium.
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Huang, K. M., L. Gullberg, K. K. Nelson, C. J. Stefan, K. Blumer, and S. K. Lemmon. "Novel functions of clathrin light chains: clathrin heavy chain trimerization is defective in light chain-deficient yeast." Journal of Cell Science 110, no. 7 (April 1, 1997): 899–910. http://dx.doi.org/10.1242/jcs.110.7.899.
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Clathrin is a major coat protein involved in sorting and retention of proteins at the late Golgi and in endocytosis from the cell surface. The clathrin triskelion contains three heavy chains, which provide the structural backbone of the clathrin lattice and three light chains, which are thought to regulate the formation or disassembly of clathrin coats. To better understand the function of the clathrin light chain, we characterized yeast strains carrying a disruption of the clathrin light chain gene (CLC1). Light chain-deficient cells showed phenotypes similar to those displayed by yeast that have a disruption in the clathrin heavy chain gene (CHC1). In clc1-delta cells, the steady state level of the clathrin heavy chain was reduced to 20%-25% of wild-type levels and most of the heavy chain was not trimerized. If CHC1 was overexpressed in clc1-delta cells, heavy chain trimers were detected and several clc1-delta phenotypes were partially rescued. These results indicate that the light chain is important for heavy chain trimerization and the heavy chain still has some function in the absence of the light chain. In yeast, deletion of CHC1 is lethal in strains carrying the scd1-i allele, while strains carrying the scd1-v allele can survive without the heavy chain. In previous studies we isolated several multicopy suppressors of inviability of chc1-delta scd1-i cells. Surprisingly, one of these suppressors, SCD4, is identical to CLC1. Overexpression of CLC1 in viable chc1-delta scd1-v strains rescued some but not all of the phenotypes displayed by these cells. In the absence of the heavy chain, the light chain was not found in a high molecular mass complex, but still associated with membranes. These results suggest that the light chain can function independently of the clathrin heavy chain in yeast.
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Yamasaki, Tomohiro, Adrian Lita, Lumin Zhang, Victor Ruiz Rodado, Tyrone Dowdy, Mark Gilbert, and Mioara Larion. "BIMG-10. IDH1 MUTATIONS INDUCE ORGANELLE DEFECTS VIA DYSREGULATED PHOSPHOLIPIDS." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i3. http://dx.doi.org/10.1093/noajnl/vdab024.009.
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Abstract BACKGROUND Metabolic alterations of lipids have been identified as a hallmark of neoplasms, with the most prevalent being the balance between saturated fatty acid (SFA) and monosaturated fatty acid (MUFA). Stearoyl-CoA desaturase1 (SCD1), converting SFA to MUFA, is increased in many cancers, leading to worse prognosis. In glioma, the role of SCD1 remains unknown. Isocitrate dehydrogenase (IDH) mutations have been most commonly observed in glioma, but the involvement of mutant IDH in SCD1 expression also remains unknown. METHODS We conducted metabolic analysis to examine the alteration of SCD1 expression in genetically engineered glioma cell lines and normal human astrocyte (NHA). Lipid metabolic analysis was conducted by using LC-MS, Raman Imaging Microscopy and SCD1 expression was examined by Western-blotting and RT-PCR method. Electron microscopy was employed for organelle structure and genetic knock-down of SCD1 gene was performed. RESULT Herein, we uncovered increased MUFA and their phospholipids in Endoplasmic Reticulum (ER), generated by IDH1 mutation, that were responsible for Golgi and ER dilation. RNA seq data from The Cancer Genome Atlas, showed that SCD1 expression was significantly higher in IDH mutant gliomas compared with wild-type, and high SCD1 expression was associated with longer survival. Inhibition of IDH1 mutation or SCD1 silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produced IDH1 mutant-specific cellular apoptosis. CONCLUSION Collectively, our results suggest that IDH1 mutant-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications. The results of the present study may also provide novel insights into the discovery of metabolic biomarkers for IDH mutant gliomas.
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Peter, Andreas, Alexander Cegan, Silvia Wagner, Michaela Elcnerova, Alfred Königsrainer, Ingmar Königsrainer, Hans-Ulrich Häring, Erwin D. Schleicher, and Norbert Stefan. "Relationships between hepatic stearoyl-CoA desaturase-1 activity and mRNA expression with liver fat content in humans." American Journal of Physiology-Endocrinology and Metabolism 300, no. 2 (February 2011): E321—E326. http://dx.doi.org/10.1152/ajpendo.00306.2010.
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Stearoyl-CoA desaturase-1 (SCD1) has gained much interest as a future drug target to treat fatty liver and its consequences. However, there are few and inconsistent human data about expression and activity of this important enzyme. We investigated activity and expression of SCD1 and their relationships with liver fat (LF) content in human liver samples. Fifty subjects undergoing liver surgery were studied. SCD1 activity was estimated from the ratio of oleate (C18:1) to stearate (C18:0) within lipid subfractions. Furthermore, SCD1 mRNA expression and LF content were measured. Similarly to previous studies, we observed a strong positive correlation between LF content and the C18:1/C18:0 ratio in the combined fatty acid (FA) fractions ( r = 0.96, P < 0.0001), which could be interpreted as higher SCD1 activity with increasing LF. However, hepatic SCD1 mRNA expression did not correlate with LF ( r = 0.16, P = 0.13). To solve these conflicting data, we analyzed the FA composition of hepatic lipid subfractions. With increasing LF content the amount of FAs from the triglyceride (TG) fraction increased ( r = 0.96, P < 0.0001), whereas the FAs from the phospholipid (PL) fraction remained unchanged ( r = −0.17, P = 0.19). Of these two major lipid fractions, the C18:1/C18:0 ratio in TG was 16-fold higher than in PL. Supporting the SCD1 mRNA expression data, the C18:1/C18:0 ratio of the TG or PL fraction did not correlate with LF ( r = 0.26, P = 0.12 and r = 0.08, P = 0.29). We provide novel information that SCD1 activity and mRNA expression appear not to be elevated in subjects with high LF content. We suggest that the FA composition of lipid subclasses, rather than of mixed lipids, should be analyzed to estimate SCD1 activity.
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Guo, Yanyan, Zibo Xiong, Meiling Su, Limin Huang, Jinlan Liao, Hongbo Xiao, Xiaoyan Huang, and Zuying Xiong. "Positive association of SCD1 genetic variation and metabolic syndrome in dialysis patients in China." Personalized Medicine 17, no. 2 (March 2020): 111–19. http://dx.doi.org/10.2217/pme-2019-0020.
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Aim: Metabolic syndrome (MetS) diagnosed in the dialysis patients is increasingly reported which worsens the prognosis of the renal diseases. The relationship of SCD1 with MetS is largely unknown. The purpose of this study was to investigate the relationship between SCD1 polymorphism and MetS in dialysis patients. Methods: A cross-sectional study was conducted on 323 Chinese dialysis patients, and the correlation between the seven SNPs of SCD1 gene (rs10883465, rs2060792, rs1502593, rs522951, rs3071, rs3978768 and rs1393492) and MetS was analyzed. Results: One tag-SNP (rs1393492) has significantly associated with the prevalence of MetS. Dialysis patients with rs1393492 AA genotype of SCD1 are more prone to MetS (p = 0.021). Conclusion: This study shows that the rs1393492 variations of SCD1 gene are related with the development of MetS in Chinese dialysis patients.
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Binczek, Erika, Britta Jenke, Barbara Holz, Robert Heinz Günter, Mario Thevis, and Wilhelm Stoffel. "Obesity resistance of the stearoyl-CoA desaturase-deficient (scd1 -/-) mouse results from disruption of the epidermal lipid barrier and adaptive thermoregulation." Biological Chemistry 388, no. 4 (April 1, 2007): 405–18. http://dx.doi.org/10.1515/bc.2007.046.
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Abstract Targeted deletion of the stearoyl-CoA desaturase 1 gene (scd1) in mouse causes obesity resistance and a severe skin phenotype. Here, we demonstrate that SCD1 deficiency disrupts the epidermal lipid barrier and leads to uncontrolled transepidermal water loss, breakdown of adaptive thermoregulation and cold resistance, as well as a metabolic wasting syndrome. The loss of ω-hydroxylated very long-chain fatty acids (VLCFA) and ceramides substituted with ω-hydroxylated VLCFA covalently linked to corneocyte surface proteins leads to the disruption of the epidermal lipid barrier in scd1 -/- mutants. Artificial occlusion of the skin by topical lipid application largely reconstituted the epidermal barrier and also reversed dysregulation of thermogenesis and cold resistance, as well as the metabolic disturbances. Interestingly, SCD1 deficiency abolished expression of the key transcription factor Lef1, which is essential for interfollicular epidermis, sebaceous glands, and hair follicle development. Finally, the occurrence of SCD1 and a newly described hSCD5 (ACOD4) gene in humans suggests that the scd1 -/- mouse mutant might be a valuable animal model for the study of human skin diseases associated with epidermal barrier defects.
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Forney, Laura A., Kirsten P. Stone, Desiree Wanders, James M. Ntambi, and Thomas W. Gettys. "The role of suppression of hepatic SCD1 expression in the metabolic effects of dietary methionine restriction." Applied Physiology, Nutrition, and Metabolism 43, no. 2 (February 2018): 123–30. http://dx.doi.org/10.1139/apnm-2017-0404.
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Dietary methionine restriction (MR) produces concurrent increases in energy intake and expenditure, but the proportionately larger increase in energy expenditure (EE) effectively limits weight gain and adipose tissue accretion over time. Increased hepatic fibroblast growth factor-21 (FGF21) is essential to MR-dependent increases in EE, but it is unknown whether the downregulation of hepatic stearoyl-coenzyme A desaturase-1 (SCD1) by MR could also be a contributing factor. Global deletion of SCD1 mimics cold exposure in mice housed at 23 °C by compromising the insular properties of the skin. The resulting cold stress increases EE, limits fat deposition, reduces hepatic lipids, and increases insulin sensitivity by activating thermoregulatory thermogenesis. To examine the efficacy of MR in the absence of SCD1 and without cold stress, the biological efficacy of MR in Scd1−/− mice housed near thermoneutrality (28 °C) was evaluated. Compared with wild-type mice on the control diet, Scd1−/− mice were leaner, had higher EE, lower hepatic and serum triglycerides, and lower serum leptin and insulin. Although dietary MR increased adipose tissue UCP1 expression, hepatic Fgf21 messenger RNA, 24 h EE, and reduced serum triglycerides in Scd1−/− mice, it failed to reduce adiposity or produce any further reduction in hepatic triglycerides, serum insulin, or serum leptin. These findings indicate that even when thermal stress is minimized, global deletion of SCD1 mimics and effectively masks many of the metabolic responses to dietary MR. However, the retention of several key effects of dietary MR in this model indicates that SCD1 is not a mediator of the biological effects of the diet.
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Lounis, Mohamed A., Karl-F. Bergeron, Maggie S. Burhans, James M. Ntambi, and Catherine Mounier. "Oleate activates SREBP-1 signaling activity in SCD1-deficient hepatocytes." American Journal of Physiology-Endocrinology and Metabolism 313, no. 6 (December 1, 2017): E710—E720. http://dx.doi.org/10.1152/ajpendo.00151.2017.
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Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in mice induces metabolic changes in the liver characterized by a decrease in de novo lipogenesis and an increase in β-oxidation. Interestingly, Scd1-deficient mice show a decrease in the expression and maturation of the principal lipogenic transcription factor sterol receptor element binding protein-1 (SREBP-1). The mechanisms mediating this effect on de novo lipogenesis and β-oxidation have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis and β-oxidation in HepG2 cells. We also used Scd1-deficient mice and two strains of transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-specific manner. We demonstrate that the expression of β-oxidation markers increases in SCD1-deficient hepatocytes and suggest that this is due to an increase in cellular polyunsaturated fatty acid content. We also show that the changes in the level of SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the lack of oleate in SCD1-deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 expression and increase hepatic de novo lipogenesis. Finally, we show that oleate specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate in SREBP-1 signaling activity.
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Rahman, Shaikh Mizanoor, Agnieszka Dobrzyn, Seong-Ho Lee, Pawel Dobrzyn, Makoto Miyazaki, and James M. Ntambi. "Stearoyl-CoA desaturase 1 deficiency increases insulin signaling and glycogen accumulation in brown adipose tissue." American Journal of Physiology-Endocrinology and Metabolism 288, no. 2 (February 2005): E381—E387. http://dx.doi.org/10.1152/ajpendo.00314.2004.
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Stearoyl-CoA desaturase (SCD) catalyzes the synthesis of oleate (C18:1) and palmitoleate (C16:1), which are the main monounsaturated fatty acids of membrane phospholipids, triglycerides, wax esters, and cholesterol esters. Previously, we showed that SCD1 deficiency elevates insulin-signaling components and downregulates protein-tyrosine phosphatase-1B (PTP-1B) in muscle, a major insulin-sensitive tissue. Here we found that, in brown adipose tissue (BAT), another insulin-sensitive tissue, the basal tyrosine phosphorylations of insulin receptor (IR) and IR substrates (IRS-1 and IRS-2) were upregulated in SCD1 −/− mice compared with wild-type mice. The association of IRS-1 and IRS-2 with the α-p85 subunit of phosphatidylinositol 3-kinase as well as Akt-Ser473 and Akt-Thr308 phosphorylation is also elevated in the SCD1 −/− mice. The mRNA expression, protein levels, and activity of PTP-1B implicated in the attenuation of the insulin signal are reduced in the SCD1 −/− mice. The content of GLUT4 in the plasma membrane increased 2.5-fold, and this was accompanied by a 6-fold increase in glucose uptake in BAT of SCD1 −/− mice. The increased glucose uptake was associated with higher glycogen synthase activity and glycogen accumulation. In the presence of insulin, [U-14C]glucose incorporation into glycogen was increased in BAT of SCD1 −/− mice. Taken together, these studies illustrate increased insulin signaling and increased glycogen metabolism in BAT of SCD1 −/− mice.
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Wang, Hongfei, Fangxiao Dong, Ye Wang, Xu’an Wang, Defei Hong, Yingbin Liu, and Jian Zhou. "Betulinic acid induces apoptosis of gallbladder cancer cells via repressing SCD1." Acta Biochimica et Biophysica Sinica 52, no. 2 (January 8, 2020): 200–206. http://dx.doi.org/10.1093/abbs/gmz148.
Full textAbstract:
Abstract Gallbladder cancer (GBC) is the most common and aggressive malignancy of the biliary tract. Betulinic acid (BetA) has been reported to have anti-inflammatory and antitumor effects; however, the effect of BetA on GBC is still unknown. In this study, we investigated the effect of BetA on five GBC cell lines and found that BetA significantly inhibited the proliferation of NOZ cells but had little inhibitory effect on other GBC cells. BetA disturbed mitochondrial membrane potential and induced apoptosis in NOZ cells. Real-time polymerase chain reaction analysis revealed that stearoyl-coenzyme A desaturase 1 (SCD1) was highly expressed in NOZ cells but low expressed in other GBC cells. BetA inhibited SCD1 expression in a concentration-dependent manner in NOZ cells. Downregulation of SCD1 expression by RNA interference inhibited the proliferation of NOZ cells and induced cell apoptosis. Moreover, BetA inhibited the growth of xenografted tumors and suppressed SCD1 expression in nude mice. Thus, our results showed that BetA induced apoptosis through repressing SCD1 expression in GBC, suggesting that BetA might be an effective agent for the treatment of patients with GBC that highly expresses SCD1.
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Tracz-Gaszewska, Zuzanna, and Pawel Dobrzyn. "Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer." Cancers 11, no. 7 (July 5, 2019): 948. http://dx.doi.org/10.3390/cancers11070948.
Full textAbstract:
A distinctive feature of cancer cells of various origins involves alterations of the composition of lipids, with significant enrichment in monounsaturated fatty acids. These molecules, in addition to being structural components of newly formed cell membranes of intensely proliferating cancer cells, support tumorigenic signaling. An increase in the expression of stearoyl-CoA desaturase 1 (SCD1), the enzyme that converts saturated fatty acids to ∆9-monounsaturated fatty acids, has been observed in a wide range of cancer cells, and this increase is correlated with cancer aggressiveness and poor outcomes for patients. Studies have demonstrated the involvement of SCD1 in the promotion of cancer cell proliferation, migration, metastasis, and tumor growth. Many studies have reported a role for this lipogenic factor in maintaining the characteristics of cancer stem cells (i.e., the population of cells that contributes to cancer progression and resistance to chemotherapy). Importantly, both the products of SCD1 activity and its direct impact on tumorigenic pathways have been demonstrated. Based on these findings, SCD1 appears to be a significant player in the development of malignant disease and may be a promising target for anticancer therapy. Numerous chemical compounds that exert inhibitory effects on SCD1 have been developed and preclinically tested. The present review summarizes our current knowledge of the ways in which SCD1 contributes to the progression of cancer and discusses opportunities and challenges of using SCD1 inhibitors for the treatment of cancer.