Pharmacological inhibition of Stearoyl-CoA Desaturase 1 improves insulin sensitivity in insulin-resistant rat models

Issandou, Marc; Bouillot, Anne; Brusq, Jean-Marie; Forest, Marie-Claire; Grillot, Didier; Guillard, Raphaelle; Martin, Sandrine; Michiels, Christelle; Sulpice, Thierry; Daugan, Alain

doi:10.1016/j.ejphar.2009.07.004

Cited by 46 publications

(42 citation statements)

References 35 publications

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“…SCD-1 plays a crucial role in the development of obesity 23) , because SCD-1 gene deficiency in ob/ob mice reverses obesity, hyperinsulinemia and hepatic steatosis 24) ; therefore, pharmacological inhibition of SCD has been tried for the treatment of obesity and insulin resistance 25,26) . SCD activity is also regulated by many dietary, hormonal and environmental factors 27) .…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid Content in Plasma Phospholipids and Desaturase Indices in Obese Children

Saito

Okada

Abe

et al. 2011

JAT

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Aims:In obesity, fatty acid composition is altered with reduced docosahexaenoic acid (DHA) levels. Desaturating enzymes, stearoyl-CoA desaturase (SCD), delta-6 desaturase (D6D) and delta-5 desaturase (D5D) modulate fatty acid composition and are thus associated with the development of metabolic syndrome. The aim of this study was to identify the relationships among DHA content, desaturase indices and the components of metabolic syndrome in childhood obesity. Methods: Thirty-two obese children (27 male, 5 female) aged 12.0 2.6 years (mean SD), with a relative body weight greater than 120% of the standard weight for sex, age and height, were recruited. Fatty acid composition of plasma phospholipids was analyzed by gas chromatography, and the desaturase indices were assessed: SCD (

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Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid Content in Plasma Phospholipids and Desaturase Indices in Obese Children

Saito

Okada

Abe

et al. 2011

JAT

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“…It was reported that genetic deletion or pharmacological inhibition of SCD-1 prevented some metabolic disorders including obesity, insulin resistance and dyslipidemia. [11][12][13][14][16][17][18][33][34][35] The SCD-1 inhibitor may have an advantage for NASH/NAFLD other than direct effects on hepatic triglyceride synthesis.…”

Section: -23)mentioning

confidence: 99%

“…[12][13][14][15] Additionally, pharmacological inhibition of SCD-1 also improved hepatic lipid accumulation and metabolic disorders. [16][17][18] On the other hand, it was poorly understood whether SCD-1 inhibition protects crucial pathological observations of NASH such as liver injury, inflammation and fibrosis. We previously reported that novel SCD-1 inhibitors with some scaffolds were obtained, and they showed potent inhibition of SCD-1 activity in vitro and in vivo.…”

mentioning

confidence: 99%

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

Kurikawa

Takagi

Wakimoto

et al. 2013

Biological & Pharmaceutical Bulletin

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Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the biosynthesis of monounsaturated fatty acids, and their abnormality is possibly responsible for obesity, insulin resistance, hepatic steatosis and nonalcoholic steatohepatitis (NASH). A novel SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methyl benzoyl) piperi din-1-yl]pyridazine-3-carboxamide, has been obtained. The compound inhibited liver SCD-1 activity and increased liver triglyceride accumulation in mice fed with non-fat, high-sucrose diets. In order to evaluate the effects of the SCD-1 inhibitor on NASH development, rats were fed with lipogenic methionine and choline-deficient (MCD) diets for 8 weeks. The SCD-1 inhibitor was administered once-daily at a dose of 30 or 100 mg/kg/d by oral gavage. Administration of a high dose of the SCD-1 inhibitor decreased triglyceride accumulation in the liver of NASH rats by 80%. Administration of a high dose of the SCD-1 inhibitor attenuated the increase of aspartate aminotransferase (AST) and alanine transaminase (ALT) by 86% and 78%, respectively. Hepatic steatosis, hepatocellular degeneration and inflammatory cell infiltration were histologically observed in the liver of NASH rats, and administration of the SCD-1 inhibitor ameliorated these crucial observations in NASH. In summary, an SCD-1 inhibitor ameliorated hepatic triglyceride accumulation, liver injury, hepatocellular degeneration and inflammation in experimental NASH models. These results suggest that SCD-1 maybe a promising target for the treatment of NASH.Key words stearoyl-CoA desaturase-1; steatohepatitis; methionine choline-deficient diet Nonalcoholic fatty liver disease (NAFLD), which is identified with excess lipid accumulation in the liver, is strongly associated with obesity, insulin resistance, hypertension, dyslipidemia and metabolic syndrome.1,2) Most NAFLD are in prognosis, although some of these progress to nonalcoholic steatohepatitis (NASH), which is defined as a histological observation of hepatocellular degeneration, inflammation and fibrosis in liver with steatosis. Finally, some NASH patients progress to liver cirrhosis and hepatocellular carcinomas, which are at the end-stage of liver disease. It is postulated that 3 to 6% of the population indicates NASH in the United States, and it is expected that the population of NASH patients will increase in the future.2) Therefore, there is a pressing need for developing a therapeutic drug to treat NASH. There are however, no therapeutic drugs approved for treating NASH patients, although some clinical pilot studies have indicated that some compounds, including insulin sensitizers, anti-dyslipidemic drugs, anti-hypertensive drugs, anti-obesity drugs and antioxidants, were effective for NASH/NAFLD. 3-9)Stearoyl-CoA desaturase (SCD) is an endoplasmic reticulum enzyme that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acyl-CoAs. 10)SCD in conjunction with the reduced nicotinamide adenine dinucleotide phosphate (NADPH), the flavoprotein cytochrome b5 reducta...

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“…two novel classes of compounds were identified from the current uHts campaign that varied from those previously described, [30][31][32][33][34][35][36][37][38][39] both in terms of structure and biological properties. the benzimidazole class of compounds (example mF-1) demonstrated high human sCd1 selectivity over human sCd5 (>20 000-fold) and was selective against delta 5 and delta 6 desaturases (>20 000-fold).…”

Section: Figmentioning

confidence: 99%

“…23,32-34 through a rational design approach, researchers [35][36][37] have modified the original aminopyrimidine or amino thiazole core with a urea group/amido heterocycle to afford derivatives exemplified by mF-152 (see table 2). CV therapeutics has also described a structurally distinct series of sCd1 inhibitors.…”

Section: Figmentioning

confidence: 99%

High-Throughput Scintillation Proximity Assay for Stearoyl-CoA Desaturase-1

et al. 2011

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Stearoyl-CoA desaturase (SCD) catalyzes the synthesis of monounsaturated fatty acids and has been implicated in a number of disease states, including obesity and diabetes. To find small-molecule inhibitor leads, a high-throughput scintillation proximity assay (SPA) was developed using the hydrophobic binding characteristics of a glass microsphere scintillant bead to capture SCD1 from a crude lysate of recombinant SCD1 in Sf9 lysate coupled with the strong binding characteristics of an azetidine compound ([3H]AZE). The SPA assay was stable over 24 h and could detect compounds with micromolar to nanomolar potencies. A robust 1536-well high-throughput screening assay was developed with good signal-to-noise ratio (10:1) and excellent Z′ factor (0.8). A screening collection of 1.6 million compounds was screened at 11 µM, and approximately 7700 compounds were identified as initial hits, exhibiting at least 35% inhibition of [3H]AZE binding. Further screening and confirmation with an SCD enzyme activity assay led to a number of new structural leads for inhibition of the enzyme. The SPA assay complements the enzyme activity assay for SCD1 as a tool for the discovery of novel leads in drug discovery.

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Pharmacological inhibition of Stearoyl-CoA Desaturase 1 improves insulin sensitivity in insulin-resistant rat models

Cited by 46 publications

References 35 publications

Docosahexaenoic Acid Content in Plasma Phospholipids and Desaturase Indices in Obese Children

Docosahexaenoic Acid Content in Plasma Phospholipids and Desaturase Indices in Obese Children

A Novel Inhibitor of Stearoyl-CoA Desaturase-1 Attenuates Hepatic Lipid Accumulation, Liver Injury and Inflammation in Model of Nonalcoholic Steatohepatitis

High-Throughput Scintillation Proximity Assay for Stearoyl-CoA Desaturase-1

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