Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A combination of the interrelated metabolic risk factors obesity, insulin resistance, dyslipidemia, and hypertension, often described as the "metabolic syndrome," is known to increase the risk of developing cardiovascular disease and diabetes. Stearoyl-coenzyme A desaturase (SCD) activity has been implicated in the metabolic syndrome, but detailed studies of the beneficial metabolic effects of SCD deficiency have been limited. Here, we show that absence of the Scd1 gene product reduces plasma triglycerides and reduces weight gain in severely hyperlipidemic low density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Absence of SCD1 also increases insulin sensitivity, as measured by intraperitoneal glucose and insulin tolerance testing. SCD1 deficiency dramatically reduces hepatic lipid accumulation while causing more modest reductions in plasma apolipoproteins, suggesting that in conditions of sustained hyperlipidemia, SCD1 functions primarily to mediate lipid stores. In addition, absence of SCD1 partially ameliorates the undesirable hypertriglyceridemic effect of antiatherogenic liver X receptor agonists. Our results demonstrate that constitutive reduction of SCD activity improves the metabolic phenotype of LDLR-deficient mice on a Western diet.
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PMID:Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice. 1796 25

Stearoyl-CoA Desaturase-1 (SCD1) is the rate limiting enzyme catalyzing the synthesis of monounsaturated fatty acids. Variation of SCD1 activity and the ratio of saturated to unsaturated fatty acids have been implicated in a variety of diseases including obesity, type II diabetes and cancers. In liver, many factors regulate SCD1 expression including dietary and hormonal factors such as insulin and leptin. We previously showed in hepatic cells that insulin acts through the PI3K and mTOR pathways to upregulate SCD1 expression. In the present study, using HepG2 cells, we characterized the signaling pathway mediating the leptin inhibitory response on SCD1 gene expression. We showed that leptin inhibits SCD1 at the transcriptional level. Inhibition of the ERK1/2 MAPK pathway with the PD98059 reverses the effect of leptin on SCD1 expression. Our data also demonstrated that the effect of leptin is entirely independent of the effect of insulin. Using the pharmaceutical inhibitors Ag490 and SL0101, we showed that the inhibitory effect of leptin is also mediated by the Janus Kinase 2 (Jak2) and p90RSK. EMSA and transfection experiments suggest a key role for the Sp1 transcription factor, which in turn may compete for the binding of other transcription factors such as AP-1, leading to the inhibition of SCD1 transcription. Taken together, our observations showed that, independently of insulin action, leptin exerts an inhibitory effect on SCD1 transcription via a signaling pathway implicating Jak2, ERK1/2, and p90RSK which probably targets the downstream transcription factor Sp1 on the SCD1 promoter.
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PMID:Key role of the ERK1/2 MAPK pathway in the transcriptional regulation of the Stearoyl-CoA Desaturase (SCD1) gene expression in response to leptin. 2010 24

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.
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PMID:Hormonal and nutritional regulation of SCD1 gene expression. 2071 21

Saturated fatty acids, acting as ligands for toll-like receptor 4 (TLR4), induce inflammation and mediate the development of insulin resistance. Myeloid differentiation factor 88 (MyD88) is an adaptor protein for TLR4. Previously, we found MyD88-deficient mice fed a high-fat diet (HFD) exhibited a severe diabetic phenotype. Stearoyl-CoA Desaturase 1 (SCD1) is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids and known as a risk factor of diabetes. In the present study, we found SCD1 was dramatically increased in HFD-fed MyD88-deficient mice liver. This finding showed the novel linkage between MyD88 and SCD1 in the development of diabetes mellitus.
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PMID:Stearoyl-CoA Desaturase 1 (SCD1) is a key factor mediating diabetes in MyD88-deficient mice. 2232 31

Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues.
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PMID:Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation. 2555 87