scholarly journals Sequential Dynamics of Stearoyl-CoA Desaturase-1(SCD1)/Ligand Binding and Unbinding Mechanism: A Computational Study

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1435
Author(s):  
Anna B. Petroff ◽  
Rebecca L. Weir ◽  
Charles R. Yates ◽  
Joseph D. Ng ◽  
Jerome Baudry
Keyword(s):  
Molecular Dynamics ◽  
Fatty Acids ◽  
Computational Study ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Membrane Composition ◽  
Endoplasmic Reticulum Protein ◽  
Metabolic Protein ◽  
Stearoyl Coa Desaturase ◽  
Dynamic Series

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.

scholarly journals Sequential dynamics of Stearoyl-CoA Desaturase-1(SCD1) /ligand binding and unbinding mechanism: A computational study

2020 ◽  
Author(s):  
Anna B. Petroff ◽  
Rebecca L. Weir ◽  
Charles R. Yates ◽  
Joseph D. Ng ◽  
Jerome Baudry
Keyword(s):  
Molecular Dynamics ◽  
Fatty Acids ◽  
Computational Study ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Membrane Composition ◽  
Endoplasmic Reticulum Protein ◽  
Metabolic Protein ◽  
Stearoyl Coa Desaturase ◽  
Dynamic Series

AbstractStearoyl-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 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.

scholarly journals Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 948 ◽  
Author(s):  
Zuzanna Tracz-Gaszewska ◽  
Pawel Dobrzyn
Keyword(s):  
Fatty Acids ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Cancer Aggressiveness ◽  
Wide Range ◽  
Stearoyl Coa Desaturase ◽  
Poor Outcomes

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.

Role of stearoyl-CoA desaturase-1 in skeletal muscle function and metabolism

2013 ◽  
Vol 305 (7) ◽  
pp. E767-E775 ◽  
Author(s):  
Alexis D. Stamatikos ◽  
Chad M. Paton
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Lipid Metabolism ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Skeletal Muscle Function ◽  
Skeletal Muscle Lipid ◽  
Stearoyl Coa Desaturase ◽  
Scd1 Expression

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.

Induction of stearoyl-CoA desaturase protects human arterial endothelial cells against lipotoxicity

2008 ◽  
Vol 295 (2) ◽  
pp. E339-E349 ◽  
Author(s):  
Andreas Peter ◽  
Cora Weigert ◽  
Harald Staiger ◽  
Kilian Rittig ◽  
Alexander Cegan ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Fatty Acids ◽  
Endothelial Cells ◽  
Inflammatory Cytokines ◽  
Cell Apoptosis ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Hek 293 ◽  
Stearoyl Coa Desaturase ◽  
Arterial Endothelial Cells

Endothelial lipotoxicity has been implicated in the pathogenesis of multiple stages of cardiovascular disease from early endothelial dysfunction to manifest atherosclerosis and its complications. Saturated free fatty acids are the major inducers of endothelial cell apoptosis and inflammatory cytokines. In humans, the enzyme human stearoyl-CoA desaturase-1 (hSCD-1) is the limiting step of the desaturation of saturated to monounsaturated fatty acids. Since we could demonstrate the expression of SCD-1 in primary human arterial endothelial cells (HAECs), we aimed to prove a beneficial role of upregulated hSCD-1 expression. In contrast to other cells that are less susceptible to lipotoxicity, hSCD-1 was not upregulated in HAECs upon palmitate treatment. Following that, we could show that upregulation of hSCD-1 using the LXR activator TO-901317 in HAECs protects the cells against palmitate-induced lipotoxicity, cell apoptosis, and expression of inflammatory cytokines IL-6 and IL-8. Increased hSCD-1 activity was determined as increased C16:1/16:0 ratio and enhanced triglyceride storage in palmitate treated cells. The beneficial effect was clearly attributed to enhanced hSCD-1 activity. Overexpression of hSCD-1 blocked palmitate-induced cytotoxicity, and knockdown of hSCD-1 using siRNA abolished the protective effect of TO-901317 in HEK-293 cells. Additionally, inhibition of hSCD-1 with 10/12 CLA blocked the effect of TO-901317 on palmitate-induced lipotoxicity, cell apoptosis, and inflammatory cytokine induction in HAECs. We conclude that upregulation of hSCD-1 leads to a desaturation of saturated fatty acids and facilitates their esterification and storage, thereby preventing downstream effects of lipotoxicity in HAECs. These findings add a novel aspect to the atheroprotective actions of LXR activators in cardiovascular disease.

scholarly journals Stearoyl-CoA Desaturase Is Essential for Porcine Adipocyte Differentiation

2020 ◽  
Vol 21 (7) ◽  
pp. 2446
Author(s):  
Lulu Liu ◽  
Yu Wang ◽  
Xiaojuan Liang ◽  
Xiao Wu ◽  
Jiali Liu ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipocyte Differentiation ◽  
Saturated Fatty Acids ◽  
Critical Role ◽  
Lipid Synthesis ◽  
Growth Efficiency ◽  
Monounsaturated Fatty Acids ◽  
Fat Deposition ◽  
Key Enzyme ◽  
Stearoyl Coa Desaturase

Fat deposition, which influences pork production, meat quality and growth efficiency, is an economically important trait in pigs. Numerous studies have demonstrated that stearoyl-CoA desaturase (SCD), a key enzyme that catalyzes the conversion of saturated fatty acids into monounsaturated fatty acids, is associated with fatty acid composition in pigs. As SCD was observed to be significantly induced in 3T3-L1 preadipocytes differentiation, we hypothesized that it plays a role in porcine adipocyte differentiation and fat deposition. In this study, we revealed that SCD is highly expressed in adipose tissues from seven-day-old piglets, compared to its expression in tissues from four-month-old adult pigs. Moreover, we found that SCD and lipogenesis-related genes were induced significantly in differentiated porcine adipocytes. Using CRISPR/Cas9 technology, we generated SCD-/- porcine embryonic fibroblasts (PEFs) and found that the loss of SCD led to dramatically decreased transdifferentiation efficiency, as evidenced by the decreased expression of known lipid synthesis-related genes, lower levels of oil red O staining and significantly lower levels of triglyceride content. Our study demonstrates the critical role of SCD expression in porcine adipocyte differentiation and paves the way for identifying it as the promising candidate gene for less fat deposition in pigs.

scholarly journals Hepatic Stearoyl-CoA desaturase-1 deficiency-mediated activation of mTORC1- PGC-1α axis regulates ER stress during high-carbohydrate feeding

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ahmed Aljohani ◽  
Mohammad Imran Khan ◽  
Deeba N. Syed ◽  
Bonneville Abram ◽  
Sarah Lewis ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Er Stress ◽  
Metabolic Diseases ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Cellular Processes ◽  
Carbohydrate Feeding ◽  
Mtorc1 Signaling ◽  
Key Enzyme ◽  
Stearoyl Coa Desaturase

Abstract Stearoyl CoA desaturase 1 (SCD1) is a key enzyme in lipogenesis as it catalyzes the synthesis of monounsaturated fatty acids (MUFAs), mainly oleate (18:1n9) and palmitoleate (16:1n7) from saturated fatty acids (SFA), stearate (18:0) and palmitate (16:0), respectively. Studies on SCD1 deficiency in mouse models demonstrated beneficial metabolic phenotypes such as reduced adiposity and improved glucose tolerance. Even though, SCD1 represents a potential target to resolve obesity related metabolic diseases; SCD1 deficiency causes endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). The induction of ER stress in response to SCD1 deficiency is governed by the cofactor, PGC-1α. However, the mechanism by which SCD1 deficiency increases PGC-1α and subsequently induces ER stress still remains elusive. The present study demonstrates that despite reduced lipogenesis, liver specific SCD1 deficiency activates the mechanistic target of rapamycin complex 1 (mTORC1) along with induction of PGC-1α and ER stress. Further, mTORC1 inhibition attenuates SCD1 deficiency-mediated induction of both PGC-1α and ER stress. Similar observations were seen by restoring endogenously synthesized oleate, but not palmitoleate, suggesting a clear mTORC1-mediated regulation of ER stress during SCD1 deficiency. Overall, our results suggest a model whereby maintaining adequate levels of hepatic oleate is required to suppress mTORC1-mediated ER stress. In addition, the activation of mTORC1 by SCD1 deficiency reveals an important function of fatty acids in regulating different cellular processes through mTORC1 signaling.

scholarly journals Effect of <i>SCD</i> SNPs on milk production traits of Jersey cows (Brief Report)

2010 ◽  
Vol 53 (1) ◽  
pp. 116-118 ◽  
Author(s):  
H. Kulig ◽  
I. Kowalewska-Łuczak ◽  
M. Kmieć
Keyword(s):  
Fatty Acids ◽  
Milk Production ◽  
Large Scale ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Production Traits ◽  
Milk Production Traits ◽  
Gene Encoding ◽  
Stearoyl Coa Desaturase ◽  
Jersey Cows

Abstract. Studies concerning associations between candidate gene polymorphisms and milk production traits in cattle are carried out on a large scale (CITEK et al. 2007, KULIG 2005). Stearoyl-CoA desaturase (SCD) is the enzyme involved in conversion of saturated fatty acids into monounsaturated fatty acids. The gene encoding SCD was mapped to bovine chromosome 26 (CAMPBELL et al. 2001), where some QTLs for fat yield and other milk production traits as well as for somatic cells count (SCC) were also identified. Some of the SNPs identified within the SCD were significantly associated with fatty acid composition in milk and in carcass fat tissue (MOIOLI et al. 2007, TANIGUCHI et al. 2004). The effect of genotypes on milk production traits and SCC in cattle has not been reported so far. The aim of this study was therefore to establish possible associations between two SNPs in the SCD and milk production traits and SCC in Jersey cows.

scholarly journals Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

2020 ◽  
Vol 217 (5) ◽  
Author(s):  
Jeroen F.J. Bogie ◽  
Elien Grajchen ◽  
Elien Wouters ◽  
Aida Garcia Corrales ◽  
Tess Dierckx ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Ex Vivo ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Demyelinating Diseases ◽  
Efflux Transporter ◽  
Stearoyl Coa Desaturase ◽  
Phenotypic Shift ◽  
The Brain

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.

Differential Effects of Dietary Fatty Acids on Body Composition and Adiposity

2020 ◽  
Vol 16 (2) ◽  
pp. 142-154 ◽  
Author(s):  
Hadi Emamat ◽  
Zahra Yari ◽  
Hossein Farhadnejad ◽  
Parvin Mirmiran
Keyword(s):  
Fatty Acids ◽  
Body Composition ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Total Body Weight ◽  
Fat Distribution ◽  
Monounsaturated Fatty Acids ◽  
Dietary Fatty Acids ◽  
Dietary Fats ◽  
Total Body

Recent evidence has highlighted that fat accumulation, particularly abdominal fat distribution, is strongly associated with metabolic disturbance. It is also well-recognized that the metabolic responses to variations in macronutrients intake can affect body composition. Previous studies suggest that the quality of dietary fats can be considered as the main determinant of body-fat deposition, fat distribution, and body composition without altering the total body weight; however, the effects of dietary fats on body composition have controversial results. There is substantial evidence to suggest that saturated fatty acids are more obesogen than unsaturated fatty acids, and with the exception of some isomers like conjugate linoleic acid, most dietary trans fatty acids are adiposity enhancers, but there is no consensus on it yet. On the other hand, there is little evidence to indicate that higher intake of the n-3 and the n-6 polyunsaturated fatty acids can be beneficial in attenuating adiposity, and the effect of monounsaturated fatty acids on body composition is contradictory. Accordingly, the content of this review summarizes the current body of knowledge on the potential effects of the different types of dietary fatty acids on body composition and adiposity. It also refers to the putative mechanisms underlying this association and reflects on the controversy of this topic.

scholarly journals Polyunsaturated ω-3 fatty acids inhibit ACE2-controlled SARS-CoV-2 binding and cellular entry

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Goc ◽  
Aleksandra Niedzwiecki ◽  
Matthias Rath
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Eicosapentaenoic Acid ◽  
Linolenic Acid ◽  
Cathepsin L ◽  
Saturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
In Vivo Experiments ◽  
Lipid Compounds

AbstractThe strain SARS-CoV-2, newly emerged in late 2019, has been identified as the cause of COVID-19 and the pandemic declared by WHO in early 2020. Although lipids have been shown to possess antiviral efficacy, little is currently known about lipid compounds with anti-SARS-CoV-2 binding and entry properties. To address this issue, we screened, overall, 17 polyunsaturated fatty acids, monounsaturated fatty acids and saturated fatty acids, as wells as lipid-soluble vitamins. In performing target-based ligand screening utilizing the RBD-SARS-CoV-2 sequence, we observed that polyunsaturated fatty acids most effectively interfere with binding to hACE2, the receptor for SARS-CoV-2. Using a spike protein pseudo-virus, we also found that linolenic acid and eicosapentaenoic acid significantly block the entry of SARS-CoV-2. In addition, eicosapentaenoic acid showed higher efficacy than linolenic acid in reducing activity of TMPRSS2 and cathepsin L proteases, but neither of the fatty acids affected their expression at the protein level. Also, neither reduction of hACE2 activity nor binding to the hACE2 receptor upon treatment with these two fatty acids was observed. Although further in vivo experiments are warranted to validate the current findings, our study provides a new insight into the role of lipids as antiviral compounds against the SARS-CoV-2 strain.

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