Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Given the recent demonstration that oleoylethanolamide (OEA), a cannabinoid receptor-inactive N-acylethanolamine, decreases food intake by activating the nuclear receptor PPARalpha (peroxisome proliferator-activated receptor alpha) in the periphery, we here evaluated the effects of both saturated and unsaturated C18 N-acylethanolamides (C18:0; C18:1; C18:2) in mice feeding behavior after overnight starvation. Our results show stearoylethanolamide (SEA, C18:0) exerts, unlike other unsaturated C18 homologs, a marked dose-dependent anorexic effect evident already at 2 h after its intraperitoneal administration. In addition, oral administration of SEA (25 mg/kg) was also effective in reducing food consumption, an effect ascribed to the molecule itself and not to its catabolites. Moreover, although the anorexic response to oral administered SEA was not associated with changes in the levels of various hematochemical parameters (e.g., glucose, cholesterol, triglycerides, leptin) nor in liver mRNA expression of peroxisome proliferator-activated receptors (PPARs) including PPARalpha, the anorexic effect of SEA was interestingly accompanied by a reduction in liver stearoyl-CoA desaturase-1 (SCD-1) mRNA expression. As SCD-1 has been recently proposed as a molecular target for the treatment of obesity, the novel observation provided here that SEA reduces food intake in mice in a structurally selective manner, in turn, correlated with downregulation of liver SCD-1 mRNA expression, has the potential of providing new insights on a class of lipid mediators with suitable properties for the pharmacological treatment of over-eating dysfunctions.
 ...
PMID:Stearoylethanolamide exerts anorexic effects in mice via down-regulation of liver stearoyl-coenzyme A desaturase-1 mRNA expression. 1528 50

The incidence of obesity has increased sharply in recent years, making it one of the most urgent public health concerns worldwide. The hormone leptin is the central mediator in a negative feedback loop regulating energy homeostasis. Leptin administration leads to reduced food intake, increased energy expenditure, and weight loss. Leptin also mediates unique metabolic effects, specifically depleting lipid from liver and other peripheral tissues. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. We review here studies on the identification of one such component, stearoyl-CoA desaturase-1 (SCD-1), as a gene specifically repressed by leptin and discuss the role of this process in mediating the metabolic effects of leptin. Data indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome.
 ...
PMID:Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). 1533 42

SCD (stearoyl-CoA desaturase) catalyses the conversion of saturated fatty acids into mono-unsaturated fatty acids, a critical step involved in lipid metabolism and various other biological functions. In the present study, we report the identification and characterization of a human gene that encodes a novel SCD enzyme (hSCD2). The hSCD2 gene codes for a 37.5-kDa protein that shares 61% and 57% sequence identity with the human SCD1 and mouse SCD2 enzymes respectively. The recombinant hSCD2 enzyme expressed in mammalian and Sf9 insect cells efficiently catalysed desaturation of both stearoyl- and palmitoyl-CoAs to the corresponding mono-unsaturated fatty acids. In comparison with the hSCD1 gene that is predominantly expressed in liver, hSCD2 is most abundantly expressed in pancreas and brain. Additionally, hSCD2 transcripts from adult and foetal tissues exhibit different sizes because of alternative splicing in the non-coding region, suggesting that hSCD2 expression is developmentally regulated. The recombinant human SCD2 and SCD1 transiently expressed in COS-7 cells exhibited as oligomeric proteins that consist of homodimers and oligomers when resolved by SDS/PAGE. The complex formation was independent of SCD protein expression levels, as supported by a relatively constant ratio of the level of dimers and oligomers to that of the monomers from COS-7 cells transiently transfected with different amounts of SCD expression vectors. Furthermore, treatment of intact COS-7 cells with a cross-linking reagent resulted in dose-dependent increases in the levels of SCD protein and activity, suggesting that oligomerization may play an important role in regulating the stability of SCD enzymes.
 ...
PMID:Characterization of human SCD2, an oligomeric desaturase with improved stability and enzyme activity by cross-linking in intact cells. 1561 69

A sucrose-rich diet generates time-dependent metabolic disorders similar to those found in diabetes type 2. After 8 month (mo) this diet evoked in the rat an increase of blood glucose, free fatty acids (FFA) and triacylycerides (TG) without insulin modification, an interruption of liver stearoyl-CoA desaturase-1 (SCD-1) mRNA and activity increase found at 6 mo, and an enhacement of Delta6 and Delta5 desaturase mRNA and Delta6 activity. We found that the administration of troglitazone (TRO), a peroxisome-proliferator-activated receptors gamma (PPAR-gamma) agonist, for 2 mo normalized plasma FFA, TG, and glucose without altering the insulinemia. It depressed liver SCD-1 mRNA in both control and sucrose-fed rats, decreasing the 18:1n-9/18:0 ratio in serum and liver lipids, and eliminated the increasing effect on mRNA and activity of Delta6 and Delta5 desaturases. These findings evidence again that desaturases are not affected through an insulin resistant effect evoked by the sucrose-rich diet and TRO recovers the altered metabolic plasma parameters as it corresponds to a PPAR-gamma agonist, but its effect on hepatic desaturases can not be attributed to a direct action on liver by PPAR-gamma, insulin, and even by an insulin sensitizing mechanism, suggesting it would be evoked indirectly through hepatic PPAR-alpha deactivation induced by the FFA decrease.
 ...
PMID:Effect of troglitazone on the desaturases in a rat model of insulin-resistance induced by a sucrose-rich diet. 1576 35

Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.
 ...
PMID:Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? 1602 36

Both insulin and PPAR-alpha up-modulate hepatic Delta9, Delta6 and Delta5 desaturating enzymes involved in the biosynthesis of mono- and polyunsaturated fatty acids. Currently, we have examined for 9 days the independent and simultaneous effects of daily glargine insulin and fenofibrate administration on the insulinemia, glycemia, hepatic acyl-CoA oxidase activity and mRNAs and enzymatic activities of stearoyl-CoA desaturase-1 (SCD-1) and Delta5 desaturase in streptozotocin diabetic rats. Glargine insulin depressed the hyperglycemia of diabetic rats at 4h, but not after 24h of injection. Fenofibrate increased the radioimmunoreactive insulinemia in non-diabetic rats without changing the glycemia. Insulin increased the mRNAs and activities of SCD-1 and Delta5 desaturase depressed in diabetic rats. Fenofibrate increased acyl-CoA oxidase activity, and the mRNAs and activities of both desaturating enzymes in non-diabetic, diabetic and insulin-treated diabetic rats, but was less effective in the mRNAs modification of diabetic animals. Therefore, insulin, and fenofibrate through PPAR-alpha activation, enhance liver mRNAs and activities of SCD-1 and Delta5 desaturases independently and synergistically through different mechanisms. Insulin and fenofibrate independently increased the 18:1/18:0 ratio in liver lipids, increasing the fluidity of the membranes. The 20:4/18:2 ratio was maintained. Fenofibrate increased palmitic acid, but decreased stearic acid percentage in liver lipids.
 ...
PMID:Effects of fenofibrate and insulin on the biosynthesis of unsaturated fatty acids in streptozotocin diabetic rats. 1609 31

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first committed step in triacylglycerol (TAG) and phospholipid biosynthesis. GPAT activity has been identified in both ER and mitochondrial subcellular fractions. The ER activity dominates in most tissues except in liver, where the mitochondrial isoform (mtGPAT) can constitute up to 50% of the total activity. To study the in vivo effects of hepatic mtGPAT overexpression, mice were transduced with adenoviruses expressing either murine mtGPAT or a catalytically inactive variant of the enzyme. Overexpressing mtGPAT resulted in massive 12- and 7-fold accumulation of liver TAG and diacylglycerol, respectively but had no effect on phospholipid or cholesterol ester content. Histological analysis showed extensive lipid accumulation in hepatocytes. Furthermore, mtGPAT transduction markedly increased adipocyte differentiation-related protein and stearoyl-CoA desaturase-1 (SCD-1) in the liver. In line with increased SCD-1 expression, 18:1 and 16:1 in the hepatic TAG fraction increased. In addition, mtGPAT overexpression decreased ex vivo fatty acid oxidation, increased liver TAG secretion rate 2-fold, and increased plasma TAG and cholesterol levels. These results support the hypothesis that increased hepatic mtGPAT activity associated with obesity and insulin resistance contributes to increased TAG biosynthesis and inhibition of fatty acid oxidation, responses that would promote hepatic steatosis and dyslipidemia.
 ...
PMID:Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. 1650 61

Dietary CLA has been shown to enhance glucose tolerance in several animal models, but in mice it induces insulin resistance and lipodystrophy. In this study, the effects of 2 wk of diet supplementation with either 1.5% CLA or 0.2% troglitazone (TZD), an insulin-sensitizing thiazolidinedione, on glucose tolerance, lipid accumulation, and composition of both lean and Zucker diabetic fatty (fa/fa; ZDF) rats were examined. Compared with lean rats, which maintained normal glucose tolerances after 2 wk of feeding regardless of diet, ZDF rats fed a control diet (CON) had significantly worsened glucose tolerance. ZDF rats fed CLA and TZD diets, however, maintained normal glucose tolerances. In contrast to the significantly elevated lipid levels in ZDF rats fed the CON diet, concentrations of plasma FFA and TG in ZDF rats fed CLA and TZD diets were normalized. A similar reduction of plasma lipid levels was observed in lean rats fed CLA and TZD compared with lean rats fed the CON diet. Although ZDF CON rats developed significant hepatic steatosis, both CLA- and TZD-fed rats had hepatic TG levels similar to those of lean rats. Both lean and ZDF rats fed the CLA diet had reduced adipose mass compared with respective genotype controls; however, TZD had no effect. Ratios of 16:1/16:0 and 18:1/18:0 FA, surrogate markers for stearoyl-CoA desaturase-1 (SCD-1) activity, were reduced in livers of ZDF rats fed CLA and TZD diets. These results show that, like TZD, CLA normalizes glucose tolerance and plasma lipids and also improves hepatic steatosis and FA composition in ZDF rats. The effects of CLA and TZD on hepatic lipid composition suggest that the effects of these two agents on glucose tolerance may be associated with a reduction in SCD-1.
 ...
PMID:Effects of conjugated linoleic acid and troglitazone on lipid accumulation and composition in lean and Zucker diabetic fatty (fa/fa) rats. 1671 98

Fatty acid-binding proteins (FABPs) are cytosolic fatty acid chaperones that play a critical role in systemic regulation of lipid and glucose metabolism. In animals lacking the adipocyte/macrophage FABP isoforms aP2 and mal1, there is strong protection against diet-induced obesity, insulin resistance, type 2 diabetes, fatty liver disease, and hypercholesterolemic atherosclerosis. On high-fat diet, FABP-deficient mice also exhibit enhanced muscle AMP-activated kinase (AMPK) and reduced liver stearoyl-CoA desaturase-1 (SCD-1) activities. Here, we performed a cross between aP2(-/-), mal1(-/-), and leptin-deficient (ob/ob) mice to elucidate the role of leptin action on the metabolic phenotype of aP2-mal1 deficiency. The extent of obesity in the ob/ob-aP2-mal1(-/-) mice was comparable with ob/ob mice. However, despite severe obesity, ob/ob-aP2-mal1(-/-) mice remained euglycemic and demonstrated improved peripheral insulin sensitivity. There was also a striking protection from liver fatty infiltration in the ob/ob-aP2-mal1(-/-) mice with strong suppression of SCD-1 activity. On the other hand, the enhanced muscle AMPK activity in aP2-mal1(-/-) mice was lost in the ob/ob background. These results indicated that both decreased body weight and enhanced muscle AMPK activity in aP2-mal1(-/-) mice are potentially leptin dependent but improved systemic insulin sensitivity and protection from liver fatty infiltration are largely unrelated to leptin action and that insulin-sensitizing effects of FABP deficiency are, at least in part, independent of its effects on total-body adiposity.
 ...
PMID:Regulation of metabolic responses by adipocyte/macrophage Fatty Acid-binding proteins in leptin-deficient mice. 1680 58

Dietary saturated fats have often been implicated in the promotion of obesity and related disorders. It has been shown recently that saturated fats act through the transcription factor SREBP-1c (sterol regulatory element-binding protein-1c) and its requisite coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), to exert their pro-lipogenic effects. We show here that a diet high in the saturated fat stearate induces lipogenic genes in wild-type mice, with the induction of the Scd1 (stearoyl-CoA desaturase-1) gene preceding that of other lipogenic genes. However, in Scd1-/- mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1beta levels are markedly reduced. Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1alpha are induced. Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1-/- mice. Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1-/- mice. These results indicate that the desaturation of saturated fats such as stearate by SCD is an essential step mediating their induction of lipogenesis. In the absence of SCD1, stearate promotes oxidation, leading to protection from saturated fat-induced obesity. SCD1 thus serves as a molecular switch in the promotion or prevention of lipid-induced disorders brought on by consumption of excess saturated fat.
 ...
PMID:Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. 1712 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>