Regulation Of Stearoyl-CoA Desaturase 1 Research Articles

Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer, from bench to bed.

Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. The expression of SCD1 is increased in many cancers, and the altered expression contributes to the proliferation, invasion, sternness and chemoresistance of cancer cells. Recently, more evidence has been reported to further support the important role of SCD1 in cancer, and the regulation mechanism of SCD1 has also been focused. Multiple factors are involved in the regulation of SCD1, including metabolism, diet, tumor microenvironment, transcription factors, non-coding RNAs, and epigenetics modification. Moreover, SCD1 is found to be involved in regulating ferroptosis resistance. Based on these findings, SCD1 has been considered as a potential target for cancer treatment. However, the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity. This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment.

Virtual screening of gut microbiome bacteriocins as potential inhibitors of stearoyl-CoA desaturase 1 to regulate adipocyte differentiation and thermogenesis to combat obesity

The gut bacterial strains and their metabolites have been shown to play a significant role in obesity, but the molecular mechanisms underlying this association are largely unresolved. Obesity is a multifactorial problem and is controlled by various mechanisms and pathways to produce and store fat cells. Bacteriocins are secondary metabolites produced by gut bacteria to defend themselves against their competitors. Recently, they have gained great attention due to their role in metabolic disorders, including obesity. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme involved in the differentiation of adipocytes. The aim of this study is to show the regulation of SCD1 by bacteriocins and thus their importance in obesity control. We screened the human gut bacteriome for the presence of bacteriocins, predicted their structures, and showed their inhibitory role by molecular docking with SCD1. Further, to confirm the docking results, MDS of six top scoring SCD1-bacteriocin complexes were carried out for 100 ns. These six bacteriocins namely, Plantaricin S-beta, Carnolysin, Lactococcin B, Bacteriocin Iic, Plantaricin N, and Thermophilin A, with strong binding affinities, are primarily produced by bacterial strains from the Lactobacillaeacea family. These findings can be the basis of further experiments for enhanced understanding of the underlying mechanisms for obesity control, specifically bacteriocins driven regulation of the SCD1 enzyme. In addition, a consortium of bacterial strains producing these bacteriocins can be developed and used as probiotics for the amelioration of obesity and other metabolic complications. Communicated by Ramaswamy H. Sarma

Fatty acid biosynthesis and transcriptional regulation of Stearoyl-CoA Desaturase 1 (SCD1) in buffalo milk

BackgroundBuffalo milk is considered as a highly nutritious food owing to its higher contents of fatty acids (FA) and rich nutrient profile. Higher fat contents of buffalo milk make it suitable for processing to develop various healthy and nutritious products. Moreover, buffalo milk contains more unsaturated FAs (UFA) such as oleic and linolenic acid, which are important from the human health point of view owing to their desirable physiological effects. However, inadequate information is available about the chemical composition and mechanism of FA synthesis in buffalo milk. In this study, we hypothesized that expression of SCD1 gene could alter the biosynthesis of FA in epithelial cells of mammary gland and subsequently affect the FA contents in buffalo milk. We investigated the transcriptional and biological role of Stearoyl-CoA Desaturase 1 (SCD1) in the buffalo mammary epithelial cells (BMECs) during FA and triacylglycerol (TAG) synthesis.ResultsResults revealed that unsaturated fatty acid contents were much higher in concentration in buffalo milk as compared to Holstein cow. Significant increase in the expression level of FAS, ACACA, SREBP1, PPARG, GPAT, and AGPAT genes was observed in response to altered expression of SCD1 in buffalo milk. Moreover, change in SCD1 gene in BMECs also mediated the expression of genes related to FA biosynthesis subsequently leading to alter the FA composition. Overexpression of SCD1 significantly increased the expression of genes associated with FA and TAG synthesis leading to enhance FA and unsaturated FA contents in BMECs. However, down-regulation of SCD1 exhibited opposite consequences.ConclusionOur study provides mechanistic insights on transcriptional regulation of SCD1 to alter FA and TAG synthesis through directly or indirectly mediating biosynthesis and metabolic pathways in BMECs. We provide preliminary findings regarding engineering of FA contents in buffalo milk through SCD1 signaling.

Vitamin A deficiency increases the oleic acid (C18:1) levels in the kidney of high fructose diet-fed rats.

Background & objectives:Stearoyl-CoA desaturase 1 (SCD1) is a key lipogenic enzyme responsible for endogenous synthesis of monounsaturated fatty acids (MUFA) and plays a key role in various pathophysiology, including fatty liver diseases. In this experimental study the impact of vitamin A deficiency was assessed on SCD1 regulation in relation to kidney biology, under high fructose (HFr) diet-fed condition in rats.Methods:Forty male weanling (21 day old) Wistar rats were divided into four groups control, vitamin A-deficient (VAD), HFr, VAD with HFr consisting of eight rats each, except 16 for the VAD group. The groups received one of the following diets: control, VAD, HFr and VAD with HFr for 16 wk, except half of the VAD diet-fed rats were shifted to HFr diet, after eight week period.Results:Feeding of VAD diet (alone or with HFr) significantly reduced the kidney retinol (0.51, 0.44 μg/g vs. 2.1 μg/g; P<0.05), while increased oleic (C18:1) and total MUFA levels (23.3, 22.2% and 27.3, 25.4% respectively vs. 14.7 and 16.6%; P<0.05) without affecting the SCD1, both at protein and mRNA levels, when compared with HFr. Comparable, immunohistological staining for SCD1 was observed in the distal convoluted tubules. Despite an increase in MUFA, morphology, triglyceride content and markers of kidney function were not affected by VAD diet feeding.Interpretation & conclusions:Feeding of VAD diet either alone or under HFr condition increased the kidney oleic acid (C18:1) levels and thus total MUFA, which corroborated with elevated SCD1 activity index, without affecting its expression status. However, these changes did not alter the kidney morphology and function. Thus, nutrient-gene regulation in kidney biology seems to be divergent.

Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN

BackgroundDiabetic patients have a higher risk factor for colorectal cancer (CRC) metastasis. Stearoyl-CoA desaturase 1 (SCD1), the main enzyme responsible for producing monounsaturated fatty acids(MUFA) from saturated fatty acids, is frequently deregulated in both diabetes and CRC. The function and mechanism of SCD1 in metastasis of CRC and its relevance to glucose remains largely unknown.MethodsSCD1 expression levels were analyzed in human CRC tissues and the Cancer Browser database (https://genome-cancer.ucsc.edu/). CRC cell lines stably transfected with SCD1 shRNAs or vector were established to investigate the role of SCD1 in modulating migration and invasion of CRC cells. A glucose concentration gradient was set to investigate regulation of SCD1 in CRC relevant to diabetic conditions.ResultsThe clinical data analysis showed high expression of SCD1 in CRC tissues with a negative correlation with the prognosis of CRC. In vitro experiments revealed that SCD1 increased CRC progression through promoting epithelial–mesenchymal transition (EMT). Lipidomic analysis demonstrated that SCD1 increased MUFA levels and MUFA administration could rescue migration and invasion defect of CRC cells induced by SCD1 knockdown. Furthermore, SCD1-mediated progression of CRC was promoted by carbohydrate response-element binding protein (ChREBP) in response to high glucose. Mechanistically, hyperglycemia-SCD1-MUFA induced CRC cell migration and invasion by regulating PTEN.ConclusionsOur findings show that SCD1 promotes metastasis of CRC cells through MUFA production and suppressing PTEN in response to glucose, which may be a novel mechanism for diabetes-induced CRC metastasis.

MiR-192-5p regulates lipid synthesis in non-alcoholic fatty liver disease through SCD-1.

AIMTo evaluate the levels of miR-192-5p in non-alcoholic fatty liver disease (NAFLD) models and demonstrate the role of miR-192-5p in lipid accumulation.METHODSThirty Sprague Dawley rats were randomly divided into three groups, which were given a standard diet, a high-fat diet (HFD), and an HFD with injection of liraglutide. At the end of 16 weeks, hepatic miR-192-5p and stearoyl-CoA desaturase 1 (SCD-1) levels were measured. MiR-192-5p mimic and inhibitor and SCD-1 siRNA were transfected into Huh7 cells exposed to palmitic acid (PA). Lipid accumulation was evaluated by oil red O staining and triglyceride assays. Direct interaction was validated by dual-luciferase reporter gene assays.RESULTSThe HFD rats showed a 0.46-fold decrease and a 3.5-fold increase in hepatic miR-192-5p and SCD-1 protein levels compared with controls, respectively, which could be reversed after disease remission by liraglutide injection (P < 0.01). The Huh7 cells exposed to PA also showed down-regulation and up-regulation of miR-192-5p and SCD-1 protein levels, respectively (P < 0.01). Transfection with miR-192-5p mimic and inhibitor in Huh7 cells induced dramatic repression and promotion of SCD-1 protein levels, respectively (P < 0.01). Luciferase activity was suppressed and enhanced by miR-192-5p mimic and inhibitor, respectively, in wild-type SCD-1 (P < 0.01) but not in mutant SCD-1. MiR-192-5p overexpression reduced lipid accumulation significantly in PA-treated Huh7 cells, and SCD-1 siRNA transfection abrogated the lipid deposition aggravated by miR-192-5p inhibitor (P < 0.01).CONCLUSIONThis study demonstrates that miR-192-5p has a negative regulatory role in lipid synthesis, which is mediated through its direct regulation of SCD-1.

Vitamin A Improves Hyperglycemia and Glucose-Intolerance through Regulation of Intracellular Signaling Pathways and Glycogen Synthesis in WNIN/GR-Ob Obese Rat Model.

Vitamin A and its metabolites modulate insulin resistance and regulate stearoyl-CoA desaturase 1 (SCD1), which are also known to affect insulin resistance. Here, we tested, whether vitamin A-mediated changes in insulin resistance markers are associated with SCD1 regulation or not. For this purpose, 30-week old male lean and glucose-intolerant obese rats of WNIN/GR-Ob strain were given either a stock or vitamin A-enriched diet, i.e. 2.6 mg or 129 mg vitamin A/kg diet, for 14 weeks. Compared to the stock diet, vitamin A-enriched diet feeding improved hyperglycemia and glucose-clearance rate in obese rats and no such changes were seen in lean rats receiving identical diets. These changes were corroborated with concomitant increase in circulatory insulin and glycogen levels of liver and muscle (whose insulin signaling pathway genes were up-regulated) in obese rats. Further, the observed increase in muscle glycogen content in these obese rats could be explained by increased levels of the active form of glycogen synthase, the key regulator of glycogen synthesis pathway, possibly inactivated through increased phosphorylation of its upstream inhibitor, glycogen synthase kinase. However, the unaltered hepatic SCD1 protein expression (despite decreased mRNA level) and increased muscle-SCD1 expression (both at gene and protein levels) suggest that vitamin A-mediated changes on glucose metabolism are not associated with SCD1 regulation. Chronic consumption of vitamin A-enriched diet improved hyperglycemia and glucose-intolerance, possibly, through the regulation of intracellular signaling and glycogen synthesis pathways of muscle and liver, but not associated with SCD1.

Binding of polyunsaturated fatty acids to LXRα and modulation of SREBP‐1 interaction with a specific SCD1 promoter element

Stearoyl-CoA desaturase 1 (SCD1) is the rate limiting enzyme in unsaturated fatty acid biosynthesis. This enzyme has an important role in the regulation of hepatic lipogenesis and lipid oxidation, and alterations in these pathways may lead to several diseases. We examined, in HepG2 cell cultures, the mechanism of SCD1 regulation considering the involvement of two transcription factors: liver X receptor alpha (LXRα) and sterol regulatory element-binding protein-1 (SREBP-1), also investigating the effect of dietary polyunsaturated fatty acids (PUFAs) on this process. The analysis of SCD1 promoter allowed to identify a functional SREBP-1 binding site (SRE 1). LXRα activation increased SCD1 protein level through upregulation of SREBP-1 and its consequent binding to SRE 1 sequence. Polyunsaturated docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) and arachidonic acid (AA, C20:4) were able to reduce SREBP-1 binding to SCD1 promoter, while saturated stearic acid (SA, C18:0) did not give any effect. Surface plasmon resonance analysis showed a direct binding of DHA, EPA and AA to LXRα. These data indicate a direct inhibitory interaction of PUFAs with LXRα, a consequent reduction of SREBP-1 and of its binding to SCD1 promoter. This information provides a mechanism to explain the regulation of lipogenic pathways induced by PUFAs.

Response gene to complement 32 deficiency protects against high‐fat diet‐induced insulin resistance and obesity with decreased hepatic lipogenesis in mice (767.7)

The objective of this study was to determine the effects of response gene to complement 32 (RGC‐32) on the development of obesity and insulin resistance in mice. Mice with RGC‐32 deficiency (RGC32‐/‐) gained less body weight with reduced epididymal fat and liver weight compared to the wild‐type animals after a 12‐week high‐fat diet. Biochemical analysis of blood, as well as glucose and insulin tolerance tests showed that RGC32‐/‐ improved insulin sensitivity and lowered serum triacylglycerol and low‐density lipoprotein/very‐low‐density lipoprotein cholesterol concentration. Hepatic lipid accumulation was also decreased in RGC32‐/‐ mice. Additional analysis revealed that lipogenic genes sterol regulatory element (SRE) binding protein (SREBP)‐1c, fatty acid synthase, and stearoyl‐CoA desaturase‐1 (SCD1) were decreased in the livers of RGC32‐/‐ mice. Mechanistic studies using mouse primary hepatocytes showed that SCD1 regulation by RGC‐32 was SREBP‐1c‐dependent since deletion or mutation of SRE abrogated SCD1 promoter activity mediated by RGC‐32. These data demonstrate that RGC‐32 induces SREBP‐1c‐dependent hepatic lipogenesis, which is essential for the high‐fat diet‐induced obesity and insulin resistance.

Abstract 1706: Estrogen induces stearoyl-CoA desaturase expression in human MCF-7 breast carcinoma cells.

Abstract Approximately 95% of breast cancers are estrogen-dependant. Estrogen plays a crucial role in many cellular processes in estrogen-sensitive breast cancer such as carcinogenesis, production of growth factors, angiogenesis and growth stimulation. To sustain cell growth, many cancer cells exhibit an altered metabolism that is characterized by increased glycolysis and lipogenesis. We observed for the first time an up regulation of stearoyl-CoA desaturase-1 (SCD1) in response to estrogen in the hormone-dependent MCF7 human breast carcinoma cell line. SCD1 is a key enzyme in the production of monounsaturated fatty acids that are essential for membrane biogenesis. Using estrogen-starved MCF7 cells, treatment with 2 nM of estrogen induced cell proliferation, increased SCD-1 gene expression measured by qPCR (2.6±0.1 fold increase, p&amp;lt;0.05) and SCD-1 protein expression (7.2 fold increase) determined by immunoblot analysis, compared to control cells. Estrogen-induced SCD1 expression was accompanied by important changes in cellular fatty acid compositions with significant increases in the monounsaturated fatty acid content in membrane phospholipids and in SCD-1 product/substrate ratios with a 4.3±0.03 fold increase in the 16:1n-7/16:0 ratio and a 1.9±0.01 fold increase in the 18:1n-9/18:0 ratio compared to untreated cells (both p&amp;lt;0.05). Treatment of estrogen-stimulated cells with a selective SCD1 inhibitor inhibited estrogen-induced cell proliferation and prevented the estrogen-induced changes in membrane lipid composition. Overall, these results show for the first time that estrogen induces SCD-1 expression in breast carcinoma cells and suggests a crucial role for SCD1 in estrogen dependent cancer cell proliferation. SCD1 may therefore represent a potential therapeutic target for estrogen-dependent cancer. (This work was supported by the Canadian Institutes of Health Research and the Canada Research Chairs Program). Citation Format: Anissa Belkaid, Rodney J. Ouellette, Marc E. Surette. Estrogen induces stearoyl-CoA desaturase expression in human MCF-7 breast carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1706. doi:10.1158/1538-7445.AM2013-1706

Stearoyl-CoA Desaturase: A Vital Checkpoint in the Development and Progression of Obesity

Stearoyl-CoA desaturase 1 (SCD-1) is the rate-limiting enzyme that catalyses the conversion of saturated to monounsaturated fatty acids. Increased SCD-1 expression and activity has been implicated in cancer, cardiovascular diseases, insulin resistance and obesity. Studies with humans, wild-type rodents, knock-out mice and cells in culture show that SCD-1 inhibition decreases lipogenesis and increases GLUT4-mediated glucose uptake in skeletal muscle. In this review, we will evaluate the role of SCD-1 as a homeostatic check-point between glucose and fatty acid metabolism in the development and progression of obesity. In addition to the role of SCD-1 in glucose and fatty acid metabolism, we will also discuss the expression and regulation of SCD-1, its specific interactions with inflammatory responses and PPARs, the role of SCD-1 derived MUFAs in obesity and the relevance of SCD desaturation index as a predictor of obesity and metabolic syndrome. Additionally, we will explore the prospects of SCD-1 as a potential drug target for the management of obesity and related disorders.

Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase

Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in fatty acid and energy metabolism, but little is known about its nutritional regulation. Dietary methionine restriction in rats decreases hepatic Scd1 mRNA and protein, increases energy expenditure, and decreases fat-pad mass/body-weight% (FM/BW%). In humans, plasma concentrations of the methionine product, cysteine, are associated with obesity. To determine which consequences of methionine-restriction are mediated by decreased cysteine availability, we monitored obesity-related variables in 4 dietary groups for 12 weeks: control-fed (CF), methionine-restricted (MR), MR supplemented with 0.5% l-cysteine (MR+Cys) and CF+Cys rats. MR lowered weight gain and FM/BW% despite higher food intake/weight than CF, and lowered serum cysteine. Hepatic Scd1 expression was decreased, with decreased serum SCD1 activity indices (calculated from serum fatty acid profile), decreased serum insulin, leptin and triglycerides, and higher adiponectin. Cysteine supplementation (MR+Cys) essentially reversed all these phenotypes and raised serum cysteine but not methionine to CF levels. Adding extra cysteine to control diet (CF+Cys) increased serum taurine but did not affect serum cysteine, lipids, proteins, or total weight gain. FM/BW% and serum leptin were modestly decreased. Our results indicate that anti-obesity effects of MR are caused by low cysteine and that dietary sulfur amino acid composition contributes to SCD1 regulation.

Stearoyl-CoA desaturase-1 is associated with insulin resistance in morbidly obese subjects.

Animal studies have revealed the association between stearoyl-CoA desaturase 1 (SCD1) and obesity and insulin resistance. However, only a few studies have been undertaken in humans. We studied SCD1 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from morbidly obese patients and their association with insulin resistance, sterol regulatory element binding protein-1 (SREBP-1) and ATPase p97, proteins involved in SCD1 synthesis and degradation. The insulin resistance was calculated in 40 morbidly obese patients and 11 overweight controls. Measurements were made of VAT and SAT SCD1, SREBP-1 and ATPase p97 mRNA expression and protein levels. VAT and SAT SCD1 mRNA expression levels in the morbidly obese patients were significantly lower than in the controls (P = 0.006), whereas SCD1 protein levels were significantly higher (P < 0.001). In the morbidly obese patients, the VAT SCD1 protein levels were decreased in patients with higher insulin resistance (P = 0.007). However, SAT SCD1 protein levels were increased in morbidly obese patients with higher insulin resistance (P < 0.05). Multiple linear regressions in the morbidly obese patients showed that the variable associated with the SCD1 protein levels in VAT was insulin resistance, and the variables associated with SCD1 protein levels in SAT were body mass index (BMI) and ATPase p97. In conclusion, these data suggest that the regulation of SCD1 is altered in individuals with morbid obesity and that the SCD1 protein has a different regulation in the two adipose tissues, as well as being closely linked to the degree of insulin resistance.

Hormonal and nutritional regulation of SCD1 gene expression

Stearoyl-CoA Desaturase 1 (SCD1) is the rate limiting enzyme catalyzing the biosynthesis of monounsaturated fatty acids preferentially from palmitoyl-CoA and stearoyl-CoA forming respectively palmitoleyl-CoA and oleyl-CoA. These monounsaturated fatty acids are the key components of triglycerides and membrane phospholipids. Studying the regulation of SCD1 is of particular interest since alterations in phospholipids composition have been implicated in a variety of diseases including cancers, diabetes and cardiovascular disorders. Furthermore, oleic acid, the main product of SCD1 reaction, is the predominant fatty acid of human adipose tissue triacylglycerols, associating SCD1 with the development of obesity and the metabolic syndrome. In light of the key role of SCD1 in general metabolism, it is not surprising to observe a very tight and complex regulation of SCD1 gene expression in response to various parameters including hormonal and nutrient factors. In this review we analyze the anatomy and index the transcription factors that have been characterized to bind the SCD1 promoter. Then we present the current knowledge on how hormones regulate SCD1 expression with a particular interest on the role of insulin and leptin. We also describe how nutrients especially polyunsaturated fatty acids and carbohydrates modulate SCD1 gene expression.

Hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia in sucrose-fed obese rats via two pathways

The mechanism by which replacement of some dietary carbohydrates with protein during weight loss favors lipid metabolism remains obscure. In this study, we investigated the effect of an energy-restricted, high-protein/low-carbohydrate diet on lipid metabolism in obese rats. High-sucrose-induced obese rats were assigned randomly to one of two energy-restricted dietary interventions: a carbohydrate-based control diet (CD) or a high-protein diet (HPD). Lean rats of the same age were assigned as normal control. There was significantly greater improvement in fatty liver and hypertriglyceridemia with the HPD diet relative to the CD diet. Expression of genes regulated by fibroblast growth factor-21 (FGF21) and involved in liver lipolysis and lipid utilitization, such as lipase and acyl-CoA oxidase, increased in obese rats fed the HPD. Furthermore, there was an inverse correlation between levels of FGF21 gene expression (regulated by glucagon/insulin balance) and increased triglyceride concentrations in liver from obese rats. Expression of hepatic stearoyl-CoA desaturase-1 (SCD1), regulated primarily by the dietary carbohydrate, was also markedly reduced in the HPD group (similar to plasma triglyceride levels in fasting animals) relative to the CD group. In conclusion, a hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia effectively relative to a carbohydrate diet. The two cellular pathways at work behind these benefits include stimulation of hepatic lipolysis and lipid utilization mediated by FGF21 and reduction of hepatic VLDL-TG production by SCD1 regulation.

Regulation of stearoyl-CoA desaturase-1 after central and peripheral nerve lesions

BackgroundInterruption of mature axons activates a cascade of events in neuronal cell bodies which leads to various outcomes from functional regeneration in the PNS to the failure of any significant regeneration in the CNS. One factor which seems to play an important role in the molecular programs after axotomy is the stearoyl Coenzyme A-desaturase-1 (SCD-1). This enzyme is needed for the conversion of stearate into oleate. Beside its role in membrane synthesis, oleate could act as a neurotrophic factor, involved in signal transduction pathways via activation of protein kinases C.ResultsIn situ hybridization and immunohistochemistry demonstrated a strong up-regulation of SCD at mRNA and protein level in regenerating neurons of the rat facial nucleus whereas non-regenerating Clarke's and Red nucleus neurons did not show an induction of this gene.ConclusionThis differential expression points to a functionally significant role for the SCD-1 in the process of regeneration.