SCD (stearoyl-CoA desaturase (delta-9-desaturase))
2015-01-01 Amir Mehdizadeh , Shabnam Fayezi , Masoud Darabi AffiliationIdentity
HGNC
LOCATION
10q24.31
LOCUSID
ALIAS
FADS5,MSTP008,SCD1,SCDOS,hSCD1
FUSION GENES
Abstract
Despite the presence of monounsaturated fatty acids (MUFA) in the usual diet, these fatty acids may also be synthesized de novo from saturated fatty acids (SFA) through enzymatic desaturase activity (Arregui et al., 2012). Stearoyl-CoA desaturase (SCD)1 and SCD5 isozymes have been identified in human. SCD1 or ?9 desaturase is predominantly expressed in adipose tissue, meibomian, harderian and preputial glands. This enzyme is highly induced in response to high carbohydrate diet (Mauvoisin & Mounier, 2011). It has been proven that the elevated levels of SCD1 are associated with obesity, metabolic disorders and malignancies. Altogether, these findings propose SCD1 as a new therapeutic target.
DNA/RNA
Note
SCD1 gene encodes an enzyme that serves as a fatty acid synthesizing enzyme and mostly produces oleic acid from stearic acid. Transcripts with alternative polyadenlyation and sizes 3.9 and 5.2 kb has been detected for this gene.
Schematic representation of the genomic organization of exons of the SCD1 gene (17817 bp).
Description
SCD1 gene is located on chromosome 10q24.31, spans approximately 24 kb and has 6 exons and is mostly expressed in white adipose tissue and the liver (Arregui et al., 2012). The exon 1 is only 324bp while the exon 6 encodes for around 2 kb 3-untranslated region (Mauvoisin & Mounier, 2011).
Transcription
The critical region for promoter activity is located between nucleotides 496-609 upstream of the translation start site. CCAAT box is identified as an important cis-element binding site in this region (Zhang, Ge, Tran, Stenn, & Prouty, 2001). Different transcription factors such as SREBP-1c, LXR, PPAR-a, C/EBP-a, NF-1, NF-Y, AP-1, Sp1, TR and PGC1-a bind to SCD1 promoter controlling the expression level of SCD1 (Mauvoisin & Mounier, 2011).
Pseudogene
Pseudogene of this gene is located on chromosome 17 at 17p11.2. The SCD1 pseudogene has two premature in-frame stop codons and is transcriptionally inactive (Zhang, Ge, Parimoo, Stenn, & Prouty, 1999).
Proteins
Note
SCD1 is an iron containing enzyme which catalyses the oxidation of palmitoyl-CoA and stearoyl-CoA in ?9 position to produce corresponding derivatives palmitoleoyl-CoA and oleoyl-CoA, respectively. Formation of cis double bond is mediated by electeron-transfer proteins sequentially NADH-cytochrome b5 reductase, cytochrome b5 and SCD. Electrons flow from NADPH source to cytochrome b5 reductase and to the cytochrome b5 as the direct electron donor to SCD1 and finally to O2 which is reduced to H2O. The rate-limiting step in this reaction is desaturase (Zhang et al., 1999).
A schematic representation of the domain structure of SCD1 protein (359 amino acids total), which consists of cytoplasmic, transmembrane, and lumenal domains.
Description
SCD1 contains four transmembrane domain which two NH2 and COOH terminals are located in cytoplasmic side. The single cytoplasmic loop and COOH terminus collectively contain eight Histidine residues forming His box and bind to iron at the center of catalytic site of desaturase. Two ER luminal loops are relatively smaller than cytosolic loop which contain two of the three conserved His motifs. Purified SCD1 remains in 37kDa band on SDS-PAGE and His segments located in 119, 156 and 296 provide ligands for nonheme iron within the catalytic site of the SCD1 (Paton & Ntambi, 2009).
Expression
SCD1 promoter contains several transcription factor binding sites that are involved in positive or negative regulation of SCD1 gene. Sterol regulatory element-binding proteins (SREBP) are a group of transcriptional factors belonging to helix-loop-helix leucine zipper family and are responsible for regulating cholesterol, fatty acids and triglyceride synthesis enzymes (Miyazaki et al., 2004). SREBP-1a is the dominant isoform of SREBP in human cultured cells and induces SCD1 gene expression (Shimomura, Shimano, Horton, Goldstein, & Brown, 1997). Furthermore, Liver X Receptors (LXR) including LXR-? and LXR-? serve as positive inducers of SCD1 gene (Peter et al., 2008). Therefore, PPAR? in combination with LXR causes elevation in the levels of SCD1 gene expression (Hebbachi, Knight, Wiggins, Patel, & Gibbons, 2008). The involvement of PPAR? in transcriptional regulation of SCD1 has also been reported in human pancreatic cells. Specifically, MEK/ERK1/2- and EGFR-dependent pathways exerted inhibitory effect on the expression and activity of SCD1 in these cells, possibly via PPAR? activation (Byagowi et al. 2015).
Localisation
SCD1 is anchored to reticulum endoplasmic membrane (Liu, Strable, & Ntambi, 2011).
Function
SCD1 is a rate-limiting enzyme which converts SFA to MUFA mainly oleate and palmitate causing high contents of MUFA in membrane phospholipids, triclycerides and cholesterol esters (Matsui et al., 2012).
Homology
Two SCD isoforms, SCD1 and SCD5 have been identified in human. SCD1 has a high degree of homology with SCD5 in human genome. Four SCD isoforms, SCD1 to SCD4 have also been identified in mouse. SCD1 shares about 85% amino acid identity with all 4 mouse SCD isoforms, as well as with rat SCD1 and SCD2. In contrast, SCD5 shares limited homology with the rodent SCDs and appears to be unique to primates (Wang et al., 2005). [supplied by OMIM, Mar 2008]. (Leung & Kim, 2013).
Mutations
Note
SCD1 gene is located on 10q24.31 position and shows different sequence polymorphisms (SNPs). Among these polymorphisms, rs3071, rs1502593 and rs10883463 SNPs have a higher degree of mean allele frequency (MAF) and are more studied. These SNPs has been implicated in multiple aspects of lipid metabolism. Also, rare alleles of rs10883463, rs7849, rs2167444, and rs508384 are associated with decreased BMI and improved insulin sensitivity (Abdelmagid et al., 2013; Arregui et al., 2012; Gong et al., 2011).
Implicated in
Entity name
Breast cancer
Note
Over-expression of SCD1 is associated with enhanced growth rate of breast cancer cell lines and shorter overall survival and relapse-free survival (RFS) in breast cancer patients (Holder et al., 2013). Furthermore, it is demonstrated that high desaturation index has a negative correlation with the risk of breast cancer (Chajs et al., 1999). Down-regulation of SCD1 by specific siRNA also leads to reduction of proliferation rate, cell cycles gene expression and phosphorylation state of ERK1/2 (Mauvoisin, Charfi, Lounis, Rassart, & Mounier, 2013). On the other hand, Mohammadzadeh et al. study revealed that inhibition of SCD1 by a selective inhibitor causes significant alteration in fatty acid composition of tissue cultured breast carcinoma in comparison to normal-appearing breast tissues and this has been attributed to the different level of SCD1 activity (Mohammadzadeh et al., 2014).
Entity name
Hepatocellular carcinoma
Note
Bansal et al. study indicated that SCD1 was significantly over-expressed in hepatocellular carcinoma (HCC) tissues in comparison to adjacent normal tissues and in HCC cell lines including HepG2, Hep3B and PLC/PLF/5. Furthermore, the level of SCD1 was negatively associated with tumour differentiation grade. Treatment of liver cancer cell lines with different panel of chemotherapeutic agents also caused over expression of SCD1 in a time dependent manner and the consequent resistance to drug induced apoptosis. It is also demonstrated that inhibition of SCD1 by genetic manipulation or chemical inhibitors leads to elevated sensitivity to chemotherapeutic agents (Bansal et al., 2013).
Entity name
Colorectal cancer
Note
Recent studies have revealed that cell death is induced in colorectal cancer cells following SCD1 inhibition. This effect is most possibly mediated through caspase 3 activity and PPAR-cleavage (Minville-Walz et al., 2010). Other studies have also reported that HTC116 colon cancer cell lines are susceptible to SCD1 depletion and subsequent decreased cell viability (Mason et al., 2012).
Entity name
Esophageal cancer
Note
Shuai Guo et al. study has shown SCD1 up-regulation in esophageal cancerous tissues in comparison to adjacent normal tissues. Furthermore, tissue lipid distribution analysis revealed that MUFA/PUFA ratio is elevated in cancerous microenvironment due to over activation of SCD1 (Guo, Wang, Zhou, & Li, 2014).
Entity name
Gastric cancer
Note
Roongta et al. reported SCD1 inhibition causes tumour growth delay in a xenograft model in nude mice (Roongta et al., 2011).
Entity name
Obesity
Note
Obesity and type 2 diabetes are highly associated with abnormal lipid metabolism and intramyocellular accumulation of triglycerides. Hulver et al reported that SCD1 is up-regulated in skeletal myocytes of obese individuals. Overexpression and overactivity of SCD1 is linked to lower fatty acid ?-oxidation rate and elevation of triglyceride and MUFA synthesis in extremely obese population (Hulver et al., 2005).
Entity name
Lipotoxicity and inflammation
Note
Lipotoxicity is a common characteristic of diabetes and metabolic syndrome. It is defined by the elevation of intracellular fatty acid metabolites including diacylglycerol and ceramides leading to endoplasmic reticulum (ER) stress. This cellular stress triggers phosphorylation of insulin receptor substrates in serine/threonine residues and activation of the nuclear factor (NF)-?B pathway (Eizirik, Cardozo, & Cnop, 2008). Such signalling pathways induce an acute inflammatory response with cytokines secretion and diminished down-stream events of insulin receptor signalling cascade resulting in low-grade inflammatory state (Peter et al., 2009). Among SFA, stearate and palmitate have a high lipotoxicity potential to induce inflammation, ER stress and insulin resistance (Staiger et al., 2006). SCD1 enzyme desaturases stearate and palmitate to less toxic monounsaturated forms oleate and palmitoleate (Peter et al., 2008). Overexpression of SCD1 is also associated with increased triglyceride storage and decreased palmitate-induced apoptosis, ceramide and diacylglycerol synthesis, as well as insulin resistance (Pinnamaneni, Southgate, Febbraio, & Watt, 2006).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 23866021 | 2013 | Plasma concentration of cis9trans11 CLA in males and females is influenced by SCD1 genetic variations and hormonal contraceptives: a cross-sectional study. | Abdelmagid SA et al |
| 23139775 | 2012 | Heterogeneity of the Stearoyl-CoA desaturase-1 (SCD1) gene and metabolic risk factors in the EPIC-Potsdam study. | Arregui M et al |
| 24135379 | 2014 | Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma. | Bansal S et al |
| 25575964 | 2015 | Effect of PPARδ agonist on stearoyl-CoA desaturase 1 in human pancreatic cancer cells: role of MEK/ERK1/2 pathway. | Byagowi S et al |
| 10521790 | 1999 | Fatty-acid composition in serum phospholipids and risk of breast cancer: an incident case-control study in Sweden. | Chajès V et al |
| 18048764 | 2008 | The role for endoplasmic reticulum stress in diabetes mellitus. | Eizirik DL et al |
| 22049297 | 2011 | Genetic variation in stearoyl-CoA desaturase 1 is associated with metabolic syndrome prevalence in Costa Rican adults. | Gong J et al |
| 25091112 | 2014 | Significantly increased monounsaturated lipids relative to polyunsaturated lipids in six types of cancer microenvironment are observed by mass spectrometry imaging. | Guo S et al |
| 18079124 | 2008 | Peroxisome proliferator-activated receptor alpha deficiency abolishes the response of lipogenic gene expression to re-feeding: restoration of the normal response by activation of liver X receptor alpha. | Hebbachi AM et al |
| 23208590 | 2013 | High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients. | Holder AM et al |
| 16213227 | 2005 | Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. | Hulver MW et al |
| 23709675 | 2013 | Stearoyl co-A desaturase 1 as a ccRCC therapeutic target: death by stress. | Leung JY et al |
| 22211186 | 2011 | Stearoyl CoA desaturase 1: role in cellular inflammation and stress. | Liu X et al |
| 22457791 | 2012 | SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids. | Mason P et al |
| 22413010 | 2012 | Stearoyl-CoA desaturase-1 (SCD1) augments saturated fatty acid-induced lipid accumulation and inhibits apoptosis in cardiac myocytes. | Matsui H et al |
| 23013158 | 2013 | Decreasing stearoyl-CoA desaturase-1 expression inhibits β-catenin signaling in breast cancer cells. | Mauvoisin D et al |
| 21179554 | 2010 | Inhibition of stearoyl-CoA desaturase 1 expression induces CHOP-dependent cell death in human cancer cells. | Minville-Walz M et al |
| 15066988 | 2004 | Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. | Miyazaki M et al |
| 25013434 | 2014 | Fatty Acid Composition of Tissue Cultured Breast Carcinoma and the Effect of Stearoyl-CoA Desaturase 1 Inhibition. | Mohammadzadeh F et al |
| 19066317 | 2009 | Biochemical and physiological function of stearoyl-CoA desaturase. | Paton CM et al |
| 19478146 | 2009 | Individual stearoyl-coa desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo. | Peter A et al |
| 17033839 | 2006 | Stearoyl CoA desaturase 1 is elevated in obesity but protects against fatty acid-induced skeletal muscle insulin resistance in vitro. | Pinnamaneni SK et al |
| 21954435 | 2011 | Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy. | Roongta UV et al |
| 9062340 | 1997 | Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. | Shimomura I et al |
| 17065351 | 2006 | Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation. | Staiger K et al |
| 11415448 | 2001 | Isolation and characterization of the human stearoyl-CoA desaturase gene promoter: requirement of a conserved CCAAT cis-element. | Zhang L et al |
Other Information
Locus ID:
NCBI: 6319
MIM: 604031
HGNC: 10571
Ensembl: ENSG00000099194
Variants:
dbSNP: 6319
ClinVar: 6319
TCGA: ENSG00000099194
COSMIC: SCD
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000099194 | ENST00000370355 | O00767 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38070637 | 2024 | Identification and experimental validation of Stearoyl-CoA desaturase is a new drug therapeutic target for osteosarcoma. | 0 |
| 38167845 | 2024 | Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression. | 0 |
| 38244769 | 2024 | Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer. | 0 |
| 38355626 | 2024 | IGF2BP3 enhances lipid metabolism in cervical cancer by upregulating the expression of SCD. | 1 |
| 38362828 | 2024 | Induction of stearoyl-CoA desaturase confers cell density-dependent ferroptosis resistance in melanoma. | 0 |
| 38372484 | 2024 | Sulfotransferase SULT2B1 facilitates colon cancer metastasis by promoting SCD1-mediated lipid metabolism. | 0 |
| 38566208 | 2024 | Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells. | 0 |
| 38849435 | 2024 | FADS2 confers SCD1 inhibition resistance to cancer cells by modulating the ER stress response. | 0 |
| 38070637 | 2024 | Identification and experimental validation of Stearoyl-CoA desaturase is a new drug therapeutic target for osteosarcoma. | 0 |
| 38167845 | 2024 | Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression. | 0 |
| 38244769 | 2024 | Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer. | 0 |
| 38355626 | 2024 | IGF2BP3 enhances lipid metabolism in cervical cancer by upregulating the expression of SCD. | 1 |
| 38362828 | 2024 | Induction of stearoyl-CoA desaturase confers cell density-dependent ferroptosis resistance in melanoma. | 0 |
| 38372484 | 2024 | Sulfotransferase SULT2B1 facilitates colon cancer metastasis by promoting SCD1-mediated lipid metabolism. | 0 |
| 38566208 | 2024 | Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells. | 0 |
Citation
Amir Mehdizadeh ; Shabnam Fayezi ; Masoud Darabi
SCD (stearoyl-CoA desaturase (delta-9-desaturase))
Atlas Genet Cytogenet Oncol Haematol. 2015-01-01
Online version: http://atlasgeneticsoncology.org/gene/43887/
