The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
James M. Ntambi - One of the best experts on this subject based on the ideXlab platform.
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Stearoyl-CoA Desaturase-2 in Murine Development, Metabolism, and Disease.
International journal of molecular sciences, 2020Co-Authors: Lucas M. O’neill, Chang-an Guo, Fang Ding, Yar Xin Phang, Zhaojin Liu, Sohel Shamsuzzaman, James M. NtambiAbstract:Stearoyl-CoA Desaturase-2 (SCD2) is a member of the Stearoyl-CoA Desaturase (SCD) family of enzymes that catalyze the rate-limiting step in monounsaturated fatty acid (MUFA) synthesis. The MUFAs palmitoleoyl-CoA (16:1n7) and oleoyl-CoA (18:1n9) are the major products of SCD2. Palmitoleoyl-CoA and oleoyl-CoA have various roles, from being a source of energy to signaling molecules. Under normal feeding conditions, SCD2 is ubiquitously expressed and is the predominant SCD isoform in the brain. However, obesogenic diets highly induce SCD2 in adipose tissue, lung, and kidney. Here we provide a comprehensive review of SCD2 in mouse development, metabolism, and various diseases, such as obesity, chronic kidney disease, Alzheimer's disease, multiple sclerosis, and Parkinson's disease. In addition, we show that bone mineral density is decreased in SCD2KO mice under high-fat feeding conditions and that SCD2 is not required for preadipocyte differentiation or the expression of PPARγ in vivo despite being required in vitro.
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Stearoyl-CoA Desaturase-3 mediates the regulation of adipose and hepatic murine lipid metabolism (605.1)
The FASEB Journal, 2014Co-Authors: Laura M. Bond, Maggie S. Burhans, James M. NtambiAbstract:Stearoyl-CoA Desaturase (SCD) is a critical enzyme involved in de novo lipogenesis and catalyzes the Δ9 desaturation of saturated fatty acids. Four SCD isoforms have been identified in mouse (SCD1-...
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The role of stearoyl‐CoA Desaturase in obesity, insulin resistance, and inflammation
Annals of the New York Academy of Sciences, 2011Co-Authors: Harini Sampath, James M. NtambiAbstract:Stearoyl-CoA Desaturase 1 (SCD1) is an essential lipogenic enzyme that has been shown to play an intrinsic role in the development of obesity and related conditions, such as insulin resistance. Through the generation of various mouse models of SCD1 deficiency, we have come to understand that SCD1 plays a role, directly or indirectly, in diverse metabolic processes, including lipogenesis, fatty acid oxidation, insulin signaling, thermogenesis, and inflammation. This review will address recent advances in our understanding of this key regulator of cellular metabolic processes, including the role of SCD1 in maintaining skin barrier integrity and the role of skin SCD1 in the metabolic phenotype elicited by global SCD1 deficiency.
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Biochemical and physiological function of Stearoyl-CoA Desaturase
American journal of physiology. Endocrinology and metabolism, 2008Co-Authors: Chad M Paton, James M. NtambiAbstract:A key and highly regulated enzyme that is required for the biosynthesis of monounsaturated fatty acids is Stearoyl-CoA Desaturase (SCD), which catalyzes the D9-cis desaturation of a range of fatty ...
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Role of Stearoyl-CoA Desaturase in human metabolic disease
Future Lipidology, 2008Co-Authors: Harini Sampath, James M. NtambiAbstract:Stearoyl-CoA Desaturase (SCD) is a highly conserved Δ-9 Desaturase that converts saturated fatty acids into monounsaturated fatty acids. Mice lacking the Scd1 gene are characterized by decreased adiposity and increased lipid oxidation and insulin sensitivity in liver and skeletal muscle. Two isoforms of SCD have also been identified in humans, and there appears to be an association between SCD expression and adiposity. This review will provide a brief update of recent progress in understanding the role of SCD in mediating the progression of disease in human populations, with a special emphasis on metabolic disease.
Agnieszka Dobrzyn - One of the best experts on this subject based on the ideXlab platform.
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Stearoyl-CoA Desaturase regulates inflammatory gene expression by changing DNA methylation level in 3T3 adipocytes.
The international journal of biochemistry & cell biology, 2014Co-Authors: Malgorzata Malodobra-mazur, Pawel Dobrzyn, Anna Dziewulska, Kamil Kozinski, Katarzyna Kolczynska, Justyna Janikiewicz, Agnieszka DobrzynAbstract:Abstract Adipocytes are one of the primary sources of inflammatory cytokines that drive the low-grade inflammation associated with obesity and obesity-related diseases. Stearoyl-CoA Desaturase, a key adipogenic enzyme in rodents and humans, plays significant role in the regulation of adipocyte inflammation via a mechanism that involves the regulation of inflammatory gene expression. In the present study, we tested the hypothesis that the Stearoyl-CoA Desaturase 1-related regulation of gene expression might be driven by changes in DNA methylation. We showed that Stearoyl-CoA Desaturase 1 overexpression causes the global hypomethylation of DNA, even as early as 12 h after the induction of differentiation, with the greatest difference seen in mature adipocytes. In contrast, both the silencing of Stearoyl-CoA Desaturase 1 gene expression by siRNA and inhibition of Stearoyl-CoA Desaturase 1 activity resulted in DNA hypermethylation in 3T3-L1 adipocytes. The analysis of the promoter methylation of 22 genes that are related to the inflammatory response showed that the level of methylation of CpG sites in interleukin-10 receptor a, interleukin-4 receptor a, interleukin-6 signal transducer, and transforming growth factor β 1 promoters was strongly related to Stearoyl-CoA Desaturase 1 expression or activity. The changes in methylation at CpG promoter sites correlated with differential expression of the aforementioned genes. The results show that Stearoyl-CoA Desaturase 1 regulates the level of DNA methylation in adipocytes and suggest that the mechanism by which Stearoyl-CoA Desaturase 1 affects adipocyte inflammation may involve changes in the methylation of inflammatory genes.
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Novel substituted heteroaromatic compounds as inhibitors of Stearoyl-CoA Desaturase
Expert opinion on therapeutic patents, 2010Co-Authors: Pawel Dobrzyn, Agnieszka DobrzynAbstract:Stearoyl-CoA Desaturase 1 (SCD1) has been implicated as a novel therapeutic target for the treatment of a variety of metabolic diseases, including diabetes, obesity, hepatic steatosis, atherosclerosis and cardiovascular disease. The application WO2009129625 from Merck Frosst Canada claims novel substituted heteroaromatic compounds as inhibitors of SCD and potential drugs for the pharmacological treatment of metabolic disorders, when used alone or in combination with other drugs. Based on in vitro activity of the patented compounds, these molecules may be considered as potential SCD inhibitors and could be of therapeutic value. However, further preclinical studies are needed to evaluate their curative potential and safety before clinical development.
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Inhibition of Stearoyl-CoA Desaturase by cyclic amine derivatives
Expert Opinion on Therapeutic Patents, 2008Co-Authors: Agnieszka Dobrzyn, Pawel DobrzynAbstract:Stearoyl-CoA Desaturase (SCD) is a central enzyme responsible for the synthesis of mono-unsaturated fatty acids, mainly oleate (C18:1), a major component of tissue lipids. Recent studies have revealed that mice deficient in SCD1 have reduced tissue lipid accumulation and increased insulin sensitivity, and are resistant to diet- and leptin-deficiency-induced obesity. These facts demonstrate that SCD activity/gene expression inhibition may be a potential therapeutic target in the prevention of diabetes and the metabolic syndrome. This patent describes novel cyclic amine derivatives that inhibit SCD activity in liver and potentially may be used in combination with other drugs (e.g., PPARγ agonists, insulin or insulin mimetics, glucagon receptor antagonists, glucokinase activators). Based on their in vitro activity, it is probable that these compounds could be of therapeutic value for the treatment of disorders connected with obesity, but more experimental and clinical studies need to be done to validate thes...
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Loss of Stearoyl-CoA Desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart.
American journal of physiology. Endocrinology and metabolism, 2007Co-Authors: Pawel Dobrzyn, Agnieszka Dobrzyn, Makoto Miyazaki, Harini Sampath, James M. NtambiAbstract: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 de...
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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, 2005Co-Authors: Agnieszka Dobrzyn, Paul Cohen, Jeffrey M Friedman, Pawel Dobrzyn, Makoto Miyazaki, Seong-ho Lee, Esra Asilmaz, Grahame D Hardie, James M. NtambiAbstract: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 sensitiv...
Pawel Dobrzyn - One of the best experts on this subject based on the ideXlab platform.
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The role of Stearoyl-CoA Desaturase in the regulation of cardiac metabolism.
Postepy biochemii, 2018Co-Authors: Sabina Tabaczar, Marcin Wolosiewicz, Anna Filip, Adam Olichwier, Pawel DobrzynAbstract:The uptake and utilization of energetic substrates in the myocardium are under strict control, any disturbances of which may lead to myocardial dysfunction, such as in the case of ischemia and heart failure. Stearoyl-CoA Desaturase (SCD) is an enzyme that converts saturated fatty acids to monounsaturated fatty acids. It is an important player in the regulation of heart metabolism. Our previous studies showed that SCD1 affects substrate utilization by the heart, with a preference for glucose. Large cohort studies established a positive correlation between the plasma fatty acid desaturation index and cardiovascular disease mortality. Therefore, SCD1 might serve as a potential target for future therapies. We review recent findings on the role of SCD1 in the heart, with a focus on cardiac metabolism reprogramming and its involvement in heart dysfunction.
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Stearoyl-CoA Desaturase regulates inflammatory gene expression by changing DNA methylation level in 3T3 adipocytes.
The international journal of biochemistry & cell biology, 2014Co-Authors: Malgorzata Malodobra-mazur, Pawel Dobrzyn, Anna Dziewulska, Kamil Kozinski, Katarzyna Kolczynska, Justyna Janikiewicz, Agnieszka DobrzynAbstract:Abstract Adipocytes are one of the primary sources of inflammatory cytokines that drive the low-grade inflammation associated with obesity and obesity-related diseases. Stearoyl-CoA Desaturase, a key adipogenic enzyme in rodents and humans, plays significant role in the regulation of adipocyte inflammation via a mechanism that involves the regulation of inflammatory gene expression. In the present study, we tested the hypothesis that the Stearoyl-CoA Desaturase 1-related regulation of gene expression might be driven by changes in DNA methylation. We showed that Stearoyl-CoA Desaturase 1 overexpression causes the global hypomethylation of DNA, even as early as 12 h after the induction of differentiation, with the greatest difference seen in mature adipocytes. In contrast, both the silencing of Stearoyl-CoA Desaturase 1 gene expression by siRNA and inhibition of Stearoyl-CoA Desaturase 1 activity resulted in DNA hypermethylation in 3T3-L1 adipocytes. The analysis of the promoter methylation of 22 genes that are related to the inflammatory response showed that the level of methylation of CpG sites in interleukin-10 receptor a, interleukin-4 receptor a, interleukin-6 signal transducer, and transforming growth factor β 1 promoters was strongly related to Stearoyl-CoA Desaturase 1 expression or activity. The changes in methylation at CpG promoter sites correlated with differential expression of the aforementioned genes. The results show that Stearoyl-CoA Desaturase 1 regulates the level of DNA methylation in adipocytes and suggest that the mechanism by which Stearoyl-CoA Desaturase 1 affects adipocyte inflammation may involve changes in the methylation of inflammatory genes.
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Stearoyl-CoA Desaturase in the control of metabolic homeostasis
Postepy biochemii, 2012Co-Authors: Pawel DobrzynAbstract:Stearoyl-CoA Desaturase (SCD) is a regulatory enzyme in lipogenesis, catalyzing the rate-limiting step in the overall de novo synthesis of monounsaturated fatty acids, mainly oleate and palmitoleate from staroyl- and palmitoyl-CoA, respectively. These products are the most abundant monounsaturated fatty acids in various kinds of lipids, including phospholipids, triglicerides, cholesteryl esters, wax esters, and diacyloglycerols. SCD1 deficiency results in reduced body adiposity, increased insulin sensitivity, and resistance to diet-induced obesity. Recent studies have shown that SCD1 plays also a significant role, directly or indirectly, in the regulation of diverse metabolic processes, including lipogenesis, fatty acid oxidation, insulin signaling, thermogenesis, carcinogenesis, and inflammation. This review summarize the recent advances concerning the important role of SCD in the maintenance of metabolic homeostasis.
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Novel substituted heteroaromatic compounds as inhibitors of Stearoyl-CoA Desaturase
Expert opinion on therapeutic patents, 2010Co-Authors: Pawel Dobrzyn, Agnieszka DobrzynAbstract:Stearoyl-CoA Desaturase 1 (SCD1) has been implicated as a novel therapeutic target for the treatment of a variety of metabolic diseases, including diabetes, obesity, hepatic steatosis, atherosclerosis and cardiovascular disease. The application WO2009129625 from Merck Frosst Canada claims novel substituted heteroaromatic compounds as inhibitors of SCD and potential drugs for the pharmacological treatment of metabolic disorders, when used alone or in combination with other drugs. Based on in vitro activity of the patented compounds, these molecules may be considered as potential SCD inhibitors and could be of therapeutic value. However, further preclinical studies are needed to evaluate their curative potential and safety before clinical development.
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Inhibition of Stearoyl-CoA Desaturase by cyclic amine derivatives
Expert Opinion on Therapeutic Patents, 2008Co-Authors: Agnieszka Dobrzyn, Pawel DobrzynAbstract:Stearoyl-CoA Desaturase (SCD) is a central enzyme responsible for the synthesis of mono-unsaturated fatty acids, mainly oleate (C18:1), a major component of tissue lipids. Recent studies have revealed that mice deficient in SCD1 have reduced tissue lipid accumulation and increased insulin sensitivity, and are resistant to diet- and leptin-deficiency-induced obesity. These facts demonstrate that SCD activity/gene expression inhibition may be a potential therapeutic target in the prevention of diabetes and the metabolic syndrome. This patent describes novel cyclic amine derivatives that inhibit SCD activity in liver and potentially may be used in combination with other drugs (e.g., PPARγ agonists, insulin or insulin mimetics, glucagon receptor antagonists, glucokinase activators). Based on their in vitro activity, it is probable that these compounds could be of therapeutic value for the treatment of disorders connected with obesity, but more experimental and clinical studies need to be done to validate thes...
Renata M. Oballa - One of the best experts on this subject based on the ideXlab platform.
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Discovery of potent and liver-targeted Stearoyl-CoA Desaturase (SCD) inhibitors in a bispyrrolidine series
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Nicolas Lachance, Sébastien Guiral, Zheng Huang, Yves Gareau, Elise Isabel, Jean-philippe Leclerc, Serge Leger, Evelyn Martins, Christian Nadeau, Renata M. OballaAbstract:Inhibition of Stearoyl-CoA Desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
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Discovery of potent and liver-selective Stearoyl-CoA Desaturase (SCD) inhibitors in an acyclic linker series.
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Nicolas Lachance, Yeeman K. Ramtohul, Sébastien Guiral, Zheng Huang, Renata M. Oballa, Jean-philippe Leclerc, Hao Wang, Lei ZhangAbstract:Elevated levels of Stearoyl-CoA Desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
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SAR and optimization of thiazole analogs as potent Stearoyl-CoA Desaturase inhibitors
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Yeeman K. Ramtohul, Cameron Black, Chi-chung Chan, Sheldon Crane, Jocelyne Guay, Sébastien Guiral, Zheng Huang, Renata M. Oballa, Lei ZhangAbstract:Abstract Elevated Stearoyl-CoA Desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound 3j, a potent SCD inhibitor (human HepG2 IC50 = 1 nM) was identified from the optimization of a lead thiazole compound MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2 mg/kg, 3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.
Lei Zhang - One of the best experts on this subject based on the ideXlab platform.
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Discovery of potent and liver-selective Stearoyl-CoA Desaturase (SCD) inhibitors in an acyclic linker series.
Bioorganic & medicinal chemistry letters, 2011Co-Authors: Nicolas Lachance, Yeeman K. Ramtohul, Sébastien Guiral, Zheng Huang, Renata M. Oballa, Jean-philippe Leclerc, Hao Wang, Lei ZhangAbstract:Elevated levels of Stearoyl-CoA Desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
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SAR and optimization of thiazole analogs as potent Stearoyl-CoA Desaturase inhibitors
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Yeeman K. Ramtohul, Cameron Black, Chi-chung Chan, Sheldon Crane, Jocelyne Guay, Sébastien Guiral, Zheng Huang, Renata M. Oballa, Lei ZhangAbstract:Abstract Elevated Stearoyl-CoA Desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound 3j, a potent SCD inhibitor (human HepG2 IC50 = 1 nM) was identified from the optimization of a lead thiazole compound MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2 mg/kg, 3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.
