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INVITED REVIEW

Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

	ABSTRACT

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Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity". In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.

dexamethasone; fatty acid; glucose; lipoprotein lipase; pyruvate dehydrogenase kinase

Increasing evidence from clinical and experimental studies has established that metabolic abnormalities play a crucial role in the development of heart diseases (96, 145). Under physiological conditions, heart acquires most of its energy from metabolism of glucose and fatty acid (FA), with the latter being the major substrate consumed by cardiac tissue (145). During insulin resistance and diabetes, characterized by inadequate glucose utilization, cardiac FA consumption supersedes glucose oxidation. In the heart, elevated FA use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity" (148). During lipotoxicity, when the capacity to oxidize FA is saturated, FA accumulates and can, either by itself or via production of second messengers such as ceramides, provoke cell death (148).

Both endogenous hormones and anti-inflammatory and immunosuppressive drugs characterize glucocorticoids. Through their effects on inflammation and cellular proliferation, glucocorticoids have beneficial effects on heart disease (174). However, excessive endogenous (129, 150) and exogenous glucocorticoids (163, 169) are linked to insulin resistance. In addition, epidemiologic studies indicate that atherosclerosis and myocardial infarction occur in patients with long-term glucocorticoid treatment or Cushing's syndrome (33, 109, 187). In the present article, we will briefly review the mechanisms by which glucocorticoids induce insulin resistance; highlight their role in modulating metabolism, specifically cardiac substrate utilization; and illustrate how they may promote cardiac disease.

Glucocorticoids

The term "glucocorticoid" represents both secreted hormones and anti-inflammatory and immunosuppressive agents. As a family of therapeutic drugs, glucocorticoids have widespread use in nonendocrine and endocrine diseases (159). Today, glucocorticoids are used in a broad spectrum of anti-inflammatory and immunosuppressive therapies, which include allergic and hematological disorders, and renal, intestinal, liver, eye, and skin diseases. Rheumatic diseases and bronchial asthma are the main indications of long-term therapy with these hormones (162). In addition, glucocorticoids are also used in the suppression of the host-vs.-graft or graft-vs.-host reactions following organ transplantation surgery.

Secretion, regulation and metabolism. Historically, glucocorticoids were defined as a group of hormones released from the cortex of the adrenal gland. Secretion into the peripheral circulation occurred in a circadian fashion (800 nM in the morning and 200 nM at midnight) (188). In the human body, the main endogenous glucocorticoid is cortisol, and its basal daily secretion is 6–8 mg/m². In response to stress, cortisol release is increased up to 10-fold of the basal value (38). Endogenous glucocorticoid synthesis and release are regulated by the pituitary and hypothalamus. This regulatory system is termed the hypothalamo-pituitary-adrenal (HPA) axis (38). Under physiological conditions, the neuroendocrine neurons in the hypothalamus synthesize and secrete corticotropin-releasing hormone (CRH), which subsequently acts on the pituitary gland, causing release of adrenocorticotropic hormone (ACTH). ACTH is transported to the adrenal gland, where it stimulates secretion of glucocorticoids (Fig. 1). Increased glucocorticoids can negatively feed back and inhibit the hypothalamus and pituitary (38).

View larger version (12K): [in this window] [in a new window]   Fig. 1. Cortisol secretion, regulation and metabolism. In the human body, the main endogenous glucocorticoid is cortisol and its basal daily secretion is 6–8 mg/m2. Endogenous glucocorticoid synthesis and release is regulated by the hypothalamo-pituitary-adrenal (HPA) axis. Under physiological conditions, the neuroendocrine neurons in the hypothalamus synthesize and secrete corticotropin-releasing hormone (CRH), which subsequently acts on the pituitary gland, causing release of ACTH. ACTH is transported to the adrenal gland where it stimulates secretion of glucocorticoids. Following HPA-mediated release, glucocorticoids undergo a further intracellular conversion in peripheral tissues by 11-hydroxysteroid dehydrogenase (11-HSD). The biological action of cortisol occurs when it is in the free form (F). However, the majority of cortisol in the circulation is bound with corticosteroid-binding globulin (CBG, 90%) and albumin (6%) (B). Both cortisol and its inactive form, cortisone are metabolized by the A-ring reductases and eventually form 5- and 5-tetrahydrocortisol (5- and 5-THF) and 5-tetrahydrocortisone (THE).

The biological action of cortisol occurs when it is in the free form. However, the majority of cortisol in the circulation is bound with corticosteroid-binding globulin (CBG, 90%) and albumin (6%) (44, 195) (Fig. 1). CBG is a 383-amino acid glycoprotein, present not only in the blood but also in tissues (17). Intracellular CBG can be localized in the cells through transmembrane uptake by a membrane CBG receptor, or it can be synthesized in extrahepatic organs, like lung, ovary, and endometrium (17). The binding of cortisol to CBG restricts the access of this glucocorticoid to target cells (plasma CBG) or serves to mediate intracellular cortisol action (intracellular CBG) (17). Both cortisol and its inactive form cortisone are metabolized by hepatic A-ring reductases and eventually form 5- and 5-tetrahydrocortisol (5- and 5-THF) and 5-tetrahydrocortisone (THE) (2) (Fig. 1). The kidney excretes 95% of these metabolites, and the gut eliminates the remainder (159).

Cellular mechanism of glucocorticoid action. The molecular mechanisms of glucocorticoids have been extensively studied (155). These hormones can readily cross cellular membranes and bind with glucocorticoid (GR) or mineralocorticoid (MR) receptors in the cytosol. GR is a ligand-activated transcription factor, which is associated with "accessory proteins," for example heat shock proteins (HSP90, p60/Hop, HSP70), to form a protein complex in the absence of ligand binding (41) (Fig. 2). Following binding with glucocorticoids, GR is activated through a conformational shift and dissociation of HSPs (Fig. 2). The complex of receptor and hormone subsequently migrates into the nucleus through a nuclear pore. Homodimer of GR interacts with a specific sequence on the promoter of its target gene, called glucocorticoid response elements, causing an increase or decrease in gene expression (159) (Fig. 2). In addition, glucocorticoid-activated monomeric GR is known to induce a nontranscriptional effect through interacting with some protein factors, like nuclear factor-B (NF-B) and activating protein-1 (AP1). This mechanism may play a key role in their anti-inflammatory effects (5) (Fig. 2). In addition to their genomic effects, glucocorticoids also act via a nongenomic mechanism, which only takes a few seconds to minutes (25, 68). This nongenomic action does not require glucocorticoids to bind with their classical intracellular steroid receptors and is mediated by transmembrane receptors. During this nongenomic mechanism, numerous cellular processes are activated, including mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins) (25) (Fig. 2).

View larger version (13K): [in this window] [in a new window]   Fig. 2. Cellular mechanism of glucocorticoid action. Glucocorticoids can readily cross cellular membranes and bind with glucocorticoid receptor (GR) in the cytosol. Under inactivated conditions, GR is associated with heat shock proteins (HSP) to form a protein complex. Following binding with glucocorticoids, GR is activated through a conformational shift and dissociation of HSPs. The complex of receptor and hormone subsequently migrates into the nucleus through a nuclear pore. Homodimer of GR interacts with a specific sequence on the promoter of its target gene, which is usually called glucocorticoid response elements (GRE), causing an increase or decrease in gene expression. In contrast, glucocorticoid-activated monomeric GR is known to induce a nontranscriptional effect through interacting with some protein factors, like NF-B and activating protein-1 (AP-1). In addition to their genomic effects, glucocorticoids also act via a nongenomic mechanism, which only takes a few seconds to minutes. This nongenomic action does not require glucocorticoids to bind with their classical intracellular steroid receptors and is mediated by transmembrane receptors. During this nongenomic mechanism, numerous cellular processes are activated including mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), PKC, and heterotrimeric G proteins.

In the body, blood glucose levels are determined mainly through the balance between insulin-dependent processes like hepatic glucose production and muscle glucose utilization. Insulin resistance is a condition in which normal insulin secretion from the pancreas is insufficient to induce a biological response in these peripheral tissues. Once this disorder occurs, excess insulin is secreted from the pancreas to maintain blood glucose. Insulin resistance is associated with a large number of risk factors that also contribute to the incidence of type 2 diabetes (65). These include a family history of diabetes or gestational diabetes (76), sedentary lifestyle (171), high circulating FA (9), reduced physical activity, aging (54), tobacco smoking (35), or drugs such as steroids (170).

Glucocorticoids, as endogenous hormones and prevalent anti-inflammatory and immunosuppressive drugs, have been reported to induce Cushing's syndrome, which is characterized by central obesity and insulin resistance (159). Some more recent observations have also indicated that endogenous glucocorticoids play a key role in the incidence and development of the metabolic syndrome (111, 190). In addition, chronic treatment with synthetic glucocorticoids like dexamethasone (DEX) has been associated with hyperinsulinemia in both animal and human research (13, 151). In our laboratory, even though acute DEX injection (4 h) in rats was not associated with hyperinsulinemia, the euglycemic hyperinsulinemic clamp still showed a decrease in glucose infusion rate, suggesting the presence of whole body insulin resistance. Adrenalectomy is effective in improving insulin sensitivity in patients with hypercortisolism (119) and in Zucker fatty rats (57). Blockade of GRs by a specific inhibitor, RU-486, was able to abolish high-fat-induced insulin resistance (89). Taken together, these findings now support the possibility that systems that regulate glucocorticoids, including GR, 11-HSD1, and CBG, all play an important role in the incidence and progression of insulin resistance.

GRs and insulin resistance. GR plays a crucial role in the regulation of glucocorticoid effects. This cytoplasmic receptor family has been identified and includes three isoforms, , and , but only the GR isoform modulates the expression of glucocorticoid response element (GRE) (149). The GR gene lies on the long arm of chromosome 5, and its sequence occupies 80 kb of genomic DNA (46, 56). A positive correlation has been recognized between the expression of GR and levels of insulin resistance. For example, human skeletal muscle cells with high expression of GR suggested a reduction of insulin sensitivity (196). In patients, high levels of skeletal muscle GR mRNA were associated with hypertension and insulin resistance measured by a euglycemic hyperinsulinemic clamp (196). Mutations in the GR gene lead to a decreased glucocorticoid-binding affinity (149). Although many of these mutations have been identified as being beneficial to insulin sensitivity, there are still some mutations in the GR gene that are believed to play a role in the incidence and progression of the metabolic syndrome (149). For instance, a well-known GR mutation, Bcl/I polymorphism, has been suggested to be associated with hyperinsulinemia, visceral obesity, and hypertension (21, 192). Currently, the mechanism involved in this relationship is still unclear. Although the mechanism of hormone-independent activation is currently a subject of great interest (193), GR has been suggested to be refractory to ligand-independent activation. Unlike progesterone and estrogen receptors, GR is not activated or phosporylated via cross talk with other signal transduction pathways (116, 132). Therefore, the mechanism of glucocorticoid-independent activation is currently not considered to be a major mechanism in the development of insulin resistance. GR is one of the GR isoforms, but unlike GR, it does not bind with any glucocorticoid ligands, and therefore it fails to regulate gene transcription (141). Normally, this isoform binds with GR and interferes with its function. This unique action will limit the sensitivity of glucocorticoids (141). Currently, it is still unclear whether GR plays a role in the development of glucocorticoid induced insulin resistance.

11-HSD1 and insulin resistance. 11-HSD1 potentially contributes to obesity and insulin resistance in both rodents (103, 111) and humans (85, 98). This effect is probably related to its role in augmenting intracellular glucocorticoid action (161). 11-HSD1 activity increases in adipose tissue and decreases in the liver in several genetic obese animal models, such as obese Zucker rats (102) and ob/ob mice (101). A similar elevation of 11-HSD1 and an increased generation of cortisol from cortisone in skeletal muscle (197) and adipose tissue (138, 139) have also been identified in obese insulin-resistant humans, although plasma concentration of cortisol is not above the normal range. In transgenic mice, hepatic 11-HSD1 overexpression shows a modest insulin resistance, dyslipidemia, and hypertension but no obesity (126). The effects of selective adipose overexpression are more pronounced, with these animals demonstrating symptoms typically seen with the metabolic syndrome (111). On the contrary, whole body knockout of this enzyme (114, 115) or overexpression of 11-HSD2 (86) in mouse adipose tissues exhibited improved insulin sensitivity and resisted the development of visceral obesity on exposure to a high-fat diet. Interestingly, administration of carbenoxolone (CBX), an inhibitor of 11-HSD1 (and to some extent 11-HSD2), increased glucose utilization and uptake in the liver and led to an enhanced glucose infusion during euglycemic hyperinsulinemic clamps in healthy (189) and nonobese type 2 diabetic humans (1). However, because CBX had no effect on 11-HSD1 in adipose tissue, it did not improve insulin resistance and obesity in obese Zucker rats (104). A more recent study tested another 11-HSD1 inhibitor, "compound 544," and suggested that it lowered body weight and plasma glucose and insulin in obese mice (70). Although the association between 11-HSD1 and insulin resistance has been consistently observed in monogenic obese models and in different groups of obese subjects, it is still too early to determine the role of 11-HSD1 in the incidence and progression of insulin resistance in humans. Thus, a clinical study using obese subjects failed to confirm an increase in 11-HSD1 in adipose tissue (177). In addition, the presence of insulin resistance induced by high-fat feeding, even though adipose 11-HSD1 dropped, also challenges this conclusion (43). Finally, weight loss increases 11-HSD1 expression in human adipose tissues (176). Collectively, these studies imply that 11-HSD1 is likely not a key mechanism in all conditions of insulin resistance.

CBG and insulin resistance. As CBG restricts free glucocorticoids in the circulation and alters the quantity of hormone reaching target tissues, its levels are negatively correlated with glucocorticoid activity (17) and even insulin resistance (51). The effect of CBG is mainly dependent on its cortisol-binding capacity, affinity, and/or specificity. In animal experiments, tissue-specific reduction of CBG has been reported to augment free local corticosterone (64). Several genetic mutations induce a marked reduction of CBG affinity in humans (45, 180). However, this decreased affinity still maintained relatively normal serum-free cortisol concentrations. This result suggested that the decreased CBG affinity not only increases free cortisol release but may also stimulate the negative regulation of the HPA axis (45). Under the conditions of CBG deficiency, increased local glucocorticoids stimulate cellular proliferation and differentiation in adipose tissue (82). Therefore, in the human population, the reduction of CBG is inversely correlated with BMI, waist-to-hip ratio, and insulin resistance (51). Interestingly, overexpression of CBG in target organs cannot produce a beneficial effect in insulin resistance, as an increase in local CBG capacity will produce a compensatory response from the HPA axis, leading to increased total and free glucocorticoid levels (125). It should be noted that, unlike cortisol, most synthetic glucocorticoids (except prednisolone) have a low affinity to CBG, and they are normally bound to albumin (159). Therefore, CBG mediation has a low possibility of occurring in those insulin resistance models induced by synthetic glucocorticoid treatment.

Glucocorticoids and Peripheral Tissue Metabolism

Glucocorticoid-induced whole body insulin resistance is tightly correlated to its metabolic effects in individual organs. Currently, most investigations on glucocorticoids and peripheral metabolism have targeted skeletal muscle, liver, and adipose tissue. The metabolic events that occurred in these tissues, for example, decreased glucose utilization and increased glucose output and lipogenesis, play a key role in the incidence of whole body abnormalities in the metabolic syndrome. This section will briefly highlight the mechanisms of glucocorticoid effects on skeletal muscle, liver and adipose tissue metabolism.

Skeletal muscle. Skeletal muscle accounts for 80% of insulin-induced glucose disposal in the human body (37); thus, it is a major target for glucocorticoid-induced insulin resistance. In skeletal muscle, insulin stimulates glucose uptake, utilization, and storage. As cortisol administration did not alter the number of insulin receptors in skeletal muscle (15), it is likely that glucocorticoids alter glucose metabolism through its postreceptor effects on downstream insulin signaling or glucose utilization. Following chronic DEX treatment, even though its gene expression is unchanged, the phosphorylation of Akt/protein kinase B (PKB) induced by insulin significantly decreases (151). This reduction in insulin signal is paralleled by a decreased glucose uptake and disposal (39, 151, 183). The decreased PKB phosphorylation may be attributed to decreased insulin receptor tyrosine phosphorylation and insulin receptor substrate (IRS) protein expression (62). Interestingly, the reduction of glucose uptake in skeletal muscle was unrelated to alteration of glucose transporters GLUT1 and GLUT4 (175). Both total mRNA and content of GLUT1 in skeletal muscle remained unchanged following DEX (175). With GLUT4, although total protein and its functional fraction at the plasma membrane have been demonstrated to be normal or even increased (32, 67, 117), insulin-stimulated GLUT4 transport in soleus muscle decreases following DEX treatment (39, 194). These results suggest that glucocorticoids decrease glucose transport in skeletal muscle through a lowering of insulin-stimulated GLUT4 translocation. With regard to glycogen synthesis, both an increase and a decrease in skeletal muscle have been reported following DEX (39, 50, 151). Pyruvate dehydrogenase kinase-4 (PDK-4) is known to inactivate pyruvate dehydrogenase (PDH), a key enzyme that regulates pyruvate uptake into mitochondria, followed by oxidation (73). Glucocorticoid treatment in mice induced gene expression of forkhead-type transcription factor (FOXO) in skeletal muscle, which potentially upregulates PDK-4 and decreases glucose oxidation (60).

Decreased glucose metabolism is often correlated with elevation in FA metabolism. Thus, glucocorticoid treatment significantly increases FA transporter (CD36) gene expression (88) in gastrocnemius and FA oxidation in diaphragm muscle (183). However, the effect of glucocorticoids in controlling skeletal FA metabolism has yet to be completely elucidated. Peroxisome proliferator-activated receptor- (PPAR) is an early-response gene of glucocorticoids (95) that plays a key role in the regulation of FA metabolism. Recent studies have indicated that PPAR also contributes toward development of insulin resistance. PPAR null mice were protected from diet- and glucocorticoid-induced insulin resistance (52). In contrast, overexpressed PPAR mice exhibited an augmented FA oxidation and a decreased glucose uptake (52). Given the inhibitory effects of FA oxidation on phosphofructokinase and PDH (81), the insulin resistance induced by glucocorticoids may be associated with augmented FA utilization. Indeed, inhibition of lipid oxidation by etomoxir prevented corticosterone-induced insulin resistance in skeletal muscle (66).

Adipose tissue. Similar to skeletal muscle, glucose utilization in adipose tissue also affects whole body glucose disposal. Following DEX treatment, a GR-dependent and transcription-independent mechanism that attenuates insulin signal has been identified recently in cultured adipocytes (107). The decreased insulin sensitivity was attributed to postreceptor signaling defects (156). Thus, incubation with DEX significantly inhibits total mRNA and tyrosine phosphorylation of IRS-1 (156, 181). The decreased IRS-1 reduces activation of phosphatidylinositol 3-kinase (PI 3-kinase), which plays a key role in the regulation of GLUT4 transport (156). Although the total amount of GLUT4 protein in 3T3-L1 adipocytes was unchanged, basal and insulin-induced transport of GLUT4 decreased following DEX (156). Total GLUT1 protein decreased in this experiment (156). Interestingly, even though IRS-1 and PI 3-kinase were normalized via IRS-1 overexpression, insulin-induced impairment of glucose uptake by DEX did not significantly improve (156). The authors concluded that glucocorticoids might decrease glucose uptake through their inhibition of glucose transport rather than insulin signal transduction. A more recent investigation extended this research and found that DEX probably inhibits the activation of GLUT4 in the plasma membrane through a p38 MAPK process (8).

In addition to affecting glucose metabolism, glucocorticoids also play a key role in regulating lipid metabolism in adipose tissue. Glucocorticoids stimulate adipose differentiation and increase body fat mass. Thus, Cushing's syndrome is normally characterized by central obesity. This increased visceral fat could indirectly increase 11-HSD and reinforce local metabolic effects of glucocorticoids. Adipocyte differentiation and proliferation is also known to be associated with expression of PPAR. In vitro experiments indicated that DEX treatment triggered expression of PPAR in adipocytes (205). This increased PPAR regulates a number of downstream genes, like fatty acid-binding protein (178), adipocyte fatty acid binding-protein (aP2) (179), lipoprotein lipase (LPL) (83), diacylglycerol (184), and leptin (71, 84), thereby contributing toward lipid accumulation. More recently, GR has been identified to cross-talk with PPAR in its anti-inflammatory effects (118). Whether this combination can also occur in adipogenesis is currently unknown. It should be noted that not only do glucocorticoids mediate PPAR, but PPAR also affects glucocorticoid activity. A PPAR agonist, thiazolidinedione, inhibits 11-HSD1 and decreases the conversion of cortisone to cortisol in adipocytes (11). Glucocorticoids also influence adipokine release from adipose tissue, including adiponectin, resistin (136), and leptin (19). However, the role that these hormones play in the development of glucocorticoid-induced insulin resistance has yet to be completely elucidated (69) (185) (136).

As an early marker of differentiation and an important determinant of triglyceride (TG) storage in adipose tissue, LPL catalyzes circulating lipoprotein hydrolysis and facilitates uptake of FA into adipose tissue (112), which is eventually reesterified and stored as TG. Following DEX per se or DEX plus insulin treatment, both total mRNA and activity of LPL significantly increased in animal and human adipose tissue (58, 120). Adipose tissue from prednisolone-treated patients also indicated that the increased LPL activity following glucocorticoids might be a result of inhibiting degradation of the active-dimeric form (87). It should be noted that increased LPL in adipose tissue is not always found consistently, and opposite effects are observed in both intact animal and isolated cells (121). TG content in adipose tissue is also dependent on TG assembly from acyl-CoA and glycerol, a process mediated by acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (172). Following DEX treatment, FAS expression, activity, and gene transcription rate were significantly enhanced in human adipose tissue (191). However, this de novo lipogenesis is minor compared with FA uptake derived from plasma lipoprotein (40). Under physiological conditions, insulin decreases lipolysis in adipose tissue through the inhibition of hormone-sensitive lipase (HSL) (105). HSL can be phosphorylated and activated through stimulating a cAMP-dependent protein kinase (72). However, DEX is known to increase HSL activity in rat adipocytes through an increase in mRNA (165). This increase in HSL augments lipolysis, which could contribute to the development of insulin resistance, hypertension, and hyperlipidemia.

Liver. Liver is a key organ that contributes to insulin resistance through increasing glucose output. The liver is also the primary metabolic target of glucocorticoid action. A positive relationship has been proposed between glucocorticoid effects in the liver and whole body insulin resistance. Specific inactivation of hepatic GRs reduces elevated glucose output and improves hyperglycemia and hyperlipidemia in streptozotocin (STZ)-induced diabetic (122) and type 2 diabetic animal models (79, 97). Unlike other tissues, altered hepatic glucose metabolism following glucocorticoids involves the enhancement of glucose output and reduction of glucose utilization (66). DEX treatment does not change insulin receptor and IRS-1 (34), but it decreases PI 3-kinase activity in the liver. Whether this decreased PI 3-kinase contributes to a reduction of GLUT4 is currently unknown. Following glucose uptake and glycolysis, the PDH complex (PDC) facilitates entry of pyruvate into the mitochondria for subsequent oxidation. PDK inactivates PDC through phosphorylation of this enzyme. In cultured hepatoma cell lines, DEX treatment significantly increases PDK-4 gene and protein expression, which can be reversed by insulin (74). The FOXO may participate in the stimulation of PDK-4 (90). Following DEX treatment, activated GR and p300/CBP complex are recruited to the PDK-4 gene. FOXO factors in by interacting with p300/CBP complex to activate PDK-4 gene expression (90). Some more recent studies also demonstrated that the PPAR coactivator (PGC-1) might also be involved in the activation of PDK-4 (108). However, unlike diabetes and fasting, glucocorticoids do not directly stimulate PDK-4 gene expression through recruiting PGC-1 on the portion of the promoter (108). Interestingly, FOXO1 plays some role in the recruitment of PGC-1 (108). Whether this indirect recruitment contributes to PDK-4 gene expression is currently unclear. The inactivated PDC through PDK inhibits glucose utilization and switches the liver to synthesize glucose and store glycogen. Indeed, in in vivo experiments, DEX treatment increases glycogen in the liver (61). The elevated hepatic gluconeogenesis is associated with the effects of glucocorticoids on the rate-limiting enzymes, like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) (3, 59). Glucocorticoids enhance the gene expression of PEPCK and G-6-Pase, resulting in increased glucose output from the liver, which contributes to whole body insulin resistance (3, 59). Activation of PPAR also plays a key role in glucocorticoid-regulated gluconeogenesis. Thus, following DEX treatment, knockout of PPAR shows unchanged hepatic PEPCK and G-6-Pase, whereas reconstitution of PPAR increases these enzymes (12). Apart from PPAR, PGC-1 is another important regulator of gluconeogenesis. However, its expression appears to be regulated by PPAR. Overexpressed PGC-1 in liver caused hyperglycemia in mice with PPAR expression, but not in PPAR null animals (12).

In addition to altering glucose metabolism, glucocorticoids also promote hepatic TG storage. Normally, the TG level reflects the balance between lipogenesis and lipolysis. Some early studies have suggested that hepatic stored TG undergoes lipolysis to release FA, which is reesterified to form TG in the endoplasmic reticulum. This resynthesized TG eventually incorporates into a VLDL particle with apolipoproteins (91, 199). In this process, triglyceride hydrolase (TGH) is a key enzyme that regulates lipolysis (94), whereas diacylglycerol acyltransferase (DGAT) catalyzes the final stage of TG synthesis (24, 166). Following DEX treatment, a decrease in the expression of TGH and an increase in DGAT2 activity occurs in the liver, which is coupled with an amplified TG storage (42). Whether this increased TG storage promotes lipoprotein secretion is still controversial.

Glucocorticoids and Cardiac Metabolism

Normal cardiac metabolism. To maintain normal physiological function, heart needs to consistently produce energy in the form of ATP. This procedure may utilize various substrates, like FA, glucose, lactate, and ketone bodies, in which glucose and FA are the most important substrates consumed by cardiac tissue (123, 124, 137). Glucose oxidation provides the heart with 30% of its energy requirements (18). Following insulin-dependent glucose uptake and glycolysis, PDC facilitates pyruvate translocation and subsequent oxidation in the mitochondria. PDP activates, whereas PDK inactivates PDC, with resultant augmentation or inhibition of glucose oxidation, respectively (18) (Fig. 3). Compared with glucose, FAs are the preferred substrate consumed by cardiac tissue. FA is mainly derived through three pathways: 1) release from adipose tissue and transport to the heart after complexing with albumin (152), 2) provision through the breakdown of endogenous cardiac TG stores (127), and 3) hydrolysis of TG-rich lipoproteins by LPL positioned at the endothelial surface of the coronary lumen (14). Of these mechanisms, LPL-facilitated TG hydrolysis is suggested to be the principal source of FA for cardiac utilization (4) (Fig. 3).

View larger version (14K): [in this window] [in a new window]   Fig. 3. Cardiac metabolism. Glucose and fatty acid (FA) are the most important substrates consumed by cardiac tissue. Glucose oxidation provides the heart with 30% of its energy requirements. Following insulin-dependent glucose uptake and glycolysis, the pyruvate dehydrogenase complex (PDC) facilitates pyruvate translocation and subsequent oxidation in the mitochondria. Pyruvate dehydrogenase phosphatase (PDP) activates, whereas pyruvate dehydrogenase kinase (PDK) inactivates, PDC, with resultant augmentation or inhibition of glucose oxidation, respectively. Compared with glucose, FAs are the preferred substrate consumed by cardiac tissue. FA is derived mainly through 3 pathways: 1) release from adipose tissue and transport to the heart after complexing with albumin, 2) provision through the breakdown of endogenous cardiac triglyceride (TG) stores, and 3) hydrolysis of TG-rich lipoproteins by lipoprotein lipase (LPL) positioned at the endothelial surface of the coronary lumen. Of these mechanisms, LPL-facilitated TG hydrolysis is suggested to be the principal source of FA for cardiac utilization. iPDC, inactive PDC; aPDC, active PDC; Chy-TG, chylomicron TG.

Glucocorticoids and Cardiac FA Metabolism

FA contributes 70% of the ATP necessary for normal heart function (106, 182). During metabolic stress, such as diabetes and insulin resistance characterized by inadequate glucose utilization, cardiac FA consumption supersedes glucose oxidation. As an insulin resistance model, with decreasing glucose oxidation, elevated glucocorticoids are also associated with a dysfunction of FA metabolism in the heart (137). In the following sections, the effects of glucocorticoids on FA delivery, oxidation, and composition will be discussed.

FA delivery. Cardiac FA can be derived from three sources, as mentioned previously. Of these, FA released from TG-rich lipoproteins catalyzed by coronary luminal LPL is currently believed to be the most important for cardiac utilization (4). Endothelial cells do not synthesize LPL (23); hence, the enzyme is synthesized in cardiomyocytes (14). Secreted LPL binds to myocyte cell surface heparan sulfate proteoglycans (HSPGs) before it is translocated onto comparable HSPG binding sites on the luminal side of the vessel wall (14, 157, 168). According to in vitro experiments, DEX treatment per se does not increase LPL release from cardiomyocytes, whereas the combination of DEX and insulin significantly enhances LPL secretion from the cells (47, 48). Using an acute-DEX model, our laboratory has reported that glucocorticoid treatment leads to enlargement of the coronary LPL pool (135). This effect is associated with the enhanced LPL mRNA expression (135). More recently, our studies also indicated that DEX not only increases LPL on the coronary lumen but also augments basal and post-heparin plasma lipolytic activity (134). This finding suggests that DEX may produce transcriptional effects on LPL gene in multiple organs. Following acute DEX injection, the increased LPL is related to a progressive clearance of plasma TG (134, 135). Interestingly, this decreased TG level is not linked to changes in plasma FA (135). Given increased cardiac FA and TG following DEX (134, 135), our data suggest that augmented LPL facilitates FA delivery into the heart. It should be noted that the effects of glucocorticoids on the gene expression of FA transporters like CD36 might also contribute to this mechanism (27).

FA oxidation. According to the hypothesis of Randle et al. (137), FA competes with glucose for mitochondrial oxidation. Following the inhibition of glucose metabolism by glucocorticoids, FA oxidation in the heart is likely to be elevated. Corticosteroid treatment in cardiomyocytes increases the gene expression of carnitine palmitoyltransferase I (CPT I), which is a key enzyme that regulates FA uptake into the mitochondria (27). Our recent investigation using an in vivo model demonstrates that 4- to 8-h DEX injection increases FA oxidation in the heart (134). This increased oxidation is associated with a number of mechanisms. One of them, reported by our laboratory, is the activation of AMP-activated protein kinase (AMPK) (134). AMPK, a heterotrimeric enzyme, is known to promote FA oxidation (202). DEX, through transcriptional regulation, augments total AMPK protein, and thus phosphorylation (134). This increased phosphorylation of AMPK then increases ACC phosphorylation, and cardiac palmitate oxidation (134). In addition to AMPK, PPAR may also play a role in the increased oxidation of FA following glucocorticoids. PPAR can be activated by a high level of FA. However, in our previous study (134), the enhanced FA following DEX is not associated with any changes in PPAR gene. The short time after DEX exposure during this experiment may explain why PPAR expression did not change. However, this finding cannot exclude the possibility that DEX-induced metabolic changes were due to PPAR activation. A recent study in liver cells also indicated that FOXO1 plays a key role in the mediation of FA metabolism (7). This is probably through the effects of FOXO1 on mediating some gene expression like acyl-CoA oxidase (ACO) and PPAR (7). In the heart removed from DEX-treated animals, total FOXO1 phosphorylation decreases and nuclear FOXO1 protein increases (unpublished data). This altered FOXO1 augments ACO gene expression (unpublished data), which may also contribute to increased FA oxidation.

FA composition. Increased FA delivery following glucocorticoids alters FA composition in the heart. Some saturated (palmitate) and single unsaturated (oleic) FAs are preferred substrates utilized by the heart. Thus, changes in their composition are tightly correlated with increased FA oxidation (134). Unlike saturated FA necessary for ATP generation, polyunsaturated FA are also required to manufacture and repair cell membranes and regulate functions like heart rate, blood pressure, and clotting (78, 128). In our recent study (134), following DEX, we reported a drop in cardiac linoleic (LA) and -linolenic acid (LNA), with an increase in arachidonic acid (AA; Table 1). Given the function of glucocorticoids to inhibit phospholipase A₂, the increase in cardiac AA was unexpected (158). It is possible that, as DEX decreased LA and LNA over time, these FAs are either being oxidized or converted to AA. Other studies have reported that in rat testis, DEX can stimulate -6 desaturase, the rate-limiting enzyme for converting linoleic acid to arachidonic acid (153). In our study, as DEX inhibited cardiac -6 desaturase, it is likely that the decrease in LA and LNA is due to increased FA oxidation (134). At present, the mechanism for the increase in cardiac AA is unknown. Irrespective of the mechanism, excess amounts of AA are known to alter insulin signaling and sensitivity (78) and to induce cell death (130, 144) directly through the mitochondrial permeability transition (160) or indirectly through conversion of AA to toxic byproducts like epoxyeicosatrienoic acids (26, 93). Unlike -6 FA, DEX had limited effects on -3 FA like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reported to protect heart from cardiovascular disease (134) (Table 1).

Cardiac Metabolism and Heart Disease

Although promotion of atherosclerosis and other vascular diseases is commonly associated with diabetes and insulin resistance, increasing clinical and experimental evidence has established that metabolic abnormalities in the cardiomyocytes during glucose stress also play a crucial role in the development of heart diseases (96, 145). This specific cardiac phenotype is named "cardiomyopathy" (145). Diabetic cardiomyopathy is commonly initiated by a short-term and severe modification in fuel metabolism and is followed by a chronic myocardial damage and measurable contractile dysfunction (133). Although the mechanisms of cardiomyopathy are not completely understood, most investigators considered that this pathophysiological process is related to hyperinsulinemia, hyperglycemia, and increased FA (131). In general, hyperinsulinemia induces cardiac hypertrophy through insulin-mediated Akt-1-dependent and -independent pathways, whereas hyperglycemia mediates cardiac injury through the generation of reactive oxygen species (ROS) (131). As the most important risk factor, FA has been identified as triggering the development of cardiac hypertrophy via induction of insulin resistance or altering myocardial contractility and cell death (131).

Lipotoxicity and Cardiomyopathy

Overloaded FA contributes toward the initiation and development of cardiomyopathy. Thus, in rodent studies, specific elevation of FA uptake or utilization in the heart is associated with cardiac toxicity, in the absence of any systemic metabolic disturbances. Cardiac-specific overexpression of LPL or fatty acid transport protein-1 significantly increased FA delivery, with ensuing lipid storage, lipotoxic cardiomyopathy, and contractile dysfunction (28, 201). Augmented FA utilization by heart-specific overexpression of PPAR or ACS (acyl-CoA synthetase; an enzyme that converts FA to acyl-CoA for subsequent -oxidation) brought about cardiomyopathy and cardiac dysfunction, similar to that seen during diabetes (29, 53). In another strategy, reducing FA supply or utilization prevented the development of cardiomyopathy in obese or diabetic animals. In ZDF (Zucker diabetic fatty rodent model of genetic obesity and type 2 diabetes) rats or transgenic mice with cardiac overexpression of LPL, a PPAR agonist decreased plasma and cardiac intracellular lipids, and ameliorated cardiomyopathy (186, 204).

Lipid-induced cardiomyopathy is a complicated disorder, and several factors have been identified as being associated with its development following glucose stress (10, 49, 63, 145, 154, 173). Increased intracellular FA activates PPAR, which promotes the expression of genes involved in FA oxidation. Elevated FA oxidation increases mitochondrial action potential, leading to overproduction of ROS, cardiomyocyte damage, and cell death (apoptosis) (6, 22, 204). Another potential mechanism for lipotoxicity is accumulation of lipids, when FA uptake supercedes its oxidation, and TG are built up. Although a recent study has suggested that TG formation provides protection against the deleterious effects of fatty acyl-CoA (99), it has been established that this lipid storage is associated with lipotoxicity in both animal models and human studies (30, 164, 204). In general, changes in cardiac metabolism are observed before cardiomyopathy. For example, in STZ-induced diabetes, altered cardiac metabolism is observed as early as 4 days following diabetes induction (164), whereas evidence of cardiomyopathy is apparent only after 4–6 wk (146, 147). Recent studies also suggest that the pathophysiological process observed in diabetic heart might also occur following insulin resistance in animal models (20) and humans (200).

Glucocorticoids and Heart Disease

Due to their effects on inflammation and cellular proliferation, glucocorticoids have been considered beneficial in heart diseases (174). However, excessive endogenous (129, 150) and exogenous (163, 169) glucocorticoids are linked to insulin resistance. In addition, glucocorticoids per se have been implicated in the pathogenesis of cardiac diseases. Epidemiological studies suggest that atherosclerosis and myocardial infarction occur in patients with long-term glucocorticoid treatment or Cushing's syndrome (33, 109, 187). Recent clinical reports also indicated that glucocorticoid treatment in newborn fetuses and aged patients potentially induced cardiomyopathy (113, 203). Although this pathological process is not yet completely elucidated, some early morphological evaluations indicated that glucocorticoid-induced cardiomyopathy is characterized by increased accumulation of lipid droplets, cardiomyocyte hypertrophy, and dissolution of myofibrils (31, 36). The role of glucocorticoid signal in the development of cardiomyopathy is less clear. One investigation suggests that glucocorticoid-induced cardiomyocyte hypertrophy is probably related to cross talk between glucocorticoid signaling and hypertrophic signaling pathways (100). The enhanced glucocorticoid signal up-regulates serum- and glucocorticoid-induced kinase-1, which may augment -adrenergic-induced hypertrophy (100). Additionally, exogenous glucocorticoid treatment has been reported to induce mitochondrial dysfunction in both liver and muscle tissues (143). Whether this alteration in ATP production and mitochondrial genes also occurs in the heart following glucocorticoids is currently unknown.

Summary

Glucocorticoids have been recognized to play a key role in the development of insulin resistance. This whole body abnormality is associated with altered metabolisms in multiple organ systems, such as skeletal muscle, liver, and adipose tissues. These metabolic alterations and whole body insulin resistance are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that cardiac metabolic abnormalities per se play a crucial role in the development of heart failure. Following administration of glucocorticoids, glucose oxidation in the heart is compromised due to augmentation of PDK-4, whereas amplification of LPL increases lipoprotein triglyceride clearance, likely providing the heart with excessive FA that are then stored as intracellular triglyceride, and alters cardiac FA composition (Fig. 4). In the heart, elevated FA use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity." During lipotoxicity, when the capacity to oxidize FA is saturated, FAs accumulate and can, either by themselves or via production of second messengers such as ceramides, provoke cell death.

View larger version (8K): [in this window] [in a new window]   Fig. 4. Glucocorticoids and cardiac FA metabolism. Glucocorticoid treatment leads to enlargement of coronary and plasma LPL activity. This effect is probably associated with the enhanced mRNA expression in multiple organ systems. This increased LPL facilitates FA delivery into the heart, which subsequently augments FA oxidation and alters FA composition. Glucocorticoids, through transcriptional regulation, activate AMPK or FOXO1, which then upregulate cardiac FA oxidation. Augmented FA utilization also contributes to the alteration of FA composition. Finally, glucocorticoid treatment induced a drop in cardiac linoleic and -linolenic acid, with an increase in arachidonic acid (AA). This increased AA accumulation may produce a toxic effect in cardiomyocytes.

	FOOTNOTES

 

Address for reprint requests and other correspondence: B. Rodrigues, Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The Univ. of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3 (e-mail: rodrigue{at}interchange.ubc.ca)

	REFERENCES

TOP ABSTRACT REFERENCES

 

1. Andrews RC, Rooyackers O, Walker BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 88: 285–291, 2003.[Abstract/Free Full Text]
2. Aranoff G, Rosler A. Urinary tetrahydrocortisone and tetrahydrocortisol glucosiduronates in normal newborns, children and adults. Acta Endocrinol (Copenh) 94: 371–375, 1980.[Abstract/Free Full Text]
3. Argaud D, Zhang Q, Pan W, Maitra S, Pilkis SJ, Lange AJ. Regulation of rat liver glucose-6-phosphatase gene expression in different nutritional and hormonal states: gene structure and 5'-flanking sequence. Diabetes 45: 1563–1571, 1996.[Abstract]
4. Augustus AS, Kako Y, Yagyu H, Goldberg IJ. Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TG-derived FA. Am J Physiol Endocrinol Metab 284: E331–E339, 2003.[Abstract/Free Full Text]
5. Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 17: 245–261, 1996.[Abstract/Free Full Text]
6. Barouch LA, Gao D, Chen L, Miller KL, Xu W, Phan AC, Kittleson MM, Minhas KM, Berkowitz DE, Wei C, Hare JM. Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ Res 98: 119–124, 2006.[Abstract/Free Full Text]
7. Bastie CC, Nahle Z, McLoughlin T, Esser K, Zhang W, Unterman T, Abumrad NA. FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms. J Biol Chem 280: 14222–14229, 2005.[Abstract/Free Full Text]
8. Bazuine M, Carlotti F, Tafrechi RS, Hoeben RC, Maassen JA. Mitogen-activated protein kinase (MAPK) phosphatase-1 and -4 attenuate p38 MAPK during dexamethasone-induced insulin resistance in 3T3-L1 adipocytes. Mol Endocrinol 18: 1697–1707, 2004.[Abstract/Free Full Text]
9. Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA, Cusi K. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 54: 1640–1648, 2005.[Abstract/Free Full Text]
10. Bell DS. Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 18: 708–714, 1995.[Abstract]
11. Berger J, Tanen M, Elbrecht A, Hermanowski-Vosatka A, Moller DE, Wright SD, Thieringer R. Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity. J Biol Chem 276: 12629–12635, 2001.[Abstract/Free Full Text]
12. Bernal-Mizrachi C, Weng S, Feng C, Finck BN, Knutsen RH, Leone TC, Coleman T, Mecham RP, Kelly DP, Semenkovich CF. Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice. Nat Med 9: 1069–1075, 2003.[CrossRef][Web of Science][Medline]
13. Binnert C, Ruchat S, Nicod N, Tappy L. Dexamethasone-induced insulin resistance shows no gender difference in healthy humans. Diabetes Metab 30: 321–326, 2004.[Web of Science][Medline]
14. Blanchette-Mackie EJ, Masuno H, Dwyer NK, Olivecrona T, Scow RO. Lipoprotein lipase in myocytes and capillary endothelium of heart: immunocytochemical study. Am J Physiol Endocrinol Metab 256: E818–E828, 1989.[Abstract/Free Full Text]
15. Block NE, Buse MG. Effects of hypercortisolemia and diabetes on skeletal muscle insulin receptor function in vitro and in vivo. Am J Physiol Endocrinol Metab 256: E39–E48, 1989.[Abstract/Free Full Text]
16. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 329: 191–196, 1998.
17. Breuner CW, Orchinik M. Plasma binding proteins as mediators of corticosteroid action in vertebrates. J Endocrinol 175: 99–112, 2002.[Abstract]
18. Brownsey RW, Boone AN, Allard MF. Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms. Cardiovasc Res 34: 3–24, 1997.[Free Full Text]
19. Bruder ED, Jacobson L, Raff H. Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia. J Endocrinol 185: 477–484, 2005.[Abstract/Free Full Text]
20. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146: 5341–5349, 2005.[CrossRef][Web of Science][Medline]
21. Buemann B, Vohl MC, Chagnon M, Chagnon YC, Gagnon J, Perusse L, Dionne F, Despres JP, Tremblay A, Nadeau A, Bouchard C. Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res 5: 186–192, 1997.[Web of Science][Medline]
22. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51: 1938–1948, 2002.[Abstract/Free Full Text]
23. Camps L, Reina M, Llobera M, Vilaro S, Olivecrona T. Lipoprotein lipase: cellular origin and functional distribution. Am J Physiol Cell Physiol 258: C673–C681, 1990.[Abstract/Free Full Text]
24. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV Jr. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem 276: 38870–38876, 2001.[Abstract/Free Full Text]
25. Cato AC, Nestl A, Mink S. Rapid actions of steroid receptors in cellular signaling pathways. Sci STKE 138: RE9, 2002.
26. Chen J, Capdevila JH, Zeldin DC, Rosenberg RL. Inhibition of cardiac L-type calcium channels by epoxyeicosatrienoic acids. Mol Pharmacol 55: 288–295, 1999.[Abstract/Free Full Text]
27. Chen QM, Alexander D, Sun H, Xie L, Lin Y, Terrand J, Morrissy S, Purdom S. Corticosteroids inhibit cell death induced by doxorubicin in cardiomyocytes: induction of antiapoptosis, antioxidant, and detoxification genes. Mol Pharmacol 67: 1861–1873, 2005.[Abstract/Free Full Text]
28. Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, Weinheimer CJ, Yamada KA, Brunet S, Xu H, Nerbonne JM, Welch MJ, Fettig NM, Sharp TL, Sambandam N, Olson KM, Ory DS, Schaffer JE. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res 96: 225–233, 2005.[Abstract/Free Full Text]
29. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107: 813–822, 2001.[Web of Science][Medline]
30. Christoffersen C, Bollano E, Lindegaard ML, Bartels ED, Goetze JP, Andersen CB, Nielsen LB. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology 144: 3483–3490, 2003.[CrossRef][Web of Science][Medline]
31. Clark AF, Tandler B, Vignos PJ Jr. Glucocorticoid-induced alterations in the rabbit heart. Lab Invest 47: 603–610, 1982.[Web of Science][Medline]
32. Coderre L, Vallega GA, Pilch PF, Chipkin SR. In vivo effects of dexamethasone and sucrose on glucose transport (GLUT-4) protein tissue distribution. Am J Physiol Endocrinol Metab 271: E643–E648, 1996.[Abstract/Free Full Text]
33. Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G. Persistence of increased cardiovascular risk in patients with Cushing's disease after five years of successful cure. J Clin Endocrinol Metab 84: 2664–2672, 1999.[Abstract/Free Full Text]
34. Corporeau C, Foll CL, Taouis M, Gouygou JP, Berge JP, Delarue J. Adipose tissue compensates for defect of phosphatidylinositol 3'-kinase induced in liver and muscle by dietary fish oil in fed rats. Am J Physiol Endocrinol Metab 290: E78–E86, 2006.[Abstract/Free Full Text]
35. Corwin EJ, McCoy CS, Whetzel CA, Ceballos RM, Klein LC. Risk indicators of metabolic syndrome in young adults: a preliminary investigation on the influence of tobacco smoke exposure and gender. Heart Lung 35: 119–129, 2006.[CrossRef][Web of Science][Medline]
36. de Vries WB, van der Leij FR, Bakker JM, Kamphuis PJ, van Oosterhout MF, Schipper ME, Smid GB, Bartelds B, van Bel F. Alterations in adult rat heart after neonatal dexamethasone therapy. Pediatr Res 52: 900–906, 2002.[CrossRef][Web of Science][Medline]
37. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30: 1000–1007, 1981.[Web of Science][Medline]
38. Delbende C, Delarue C, Lefebvre H, Bunel DT, Szafarczyk A, Mocaer E, Kamoun A, Jegou S, Vaudry H. Glucocorticoids, transmitters and stress. Br J Psychiatry Suppl 15: 24–35, 1992.
39. Dimitriadis G, Leighton B, Parry-Billings M, Sasson S, Young M, Krause U, Bevan S, Piva T, Wegener G, Newsholme EA. Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle. Biochem J 321: 707–712, 1997.
40. Diraison F, Yankah V, Letexier D, Dusserre E, Jones P, Beylot M. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J Lipid Res 44: 846–853, 2003.[Abstract/Free Full Text]
41. Dittmar KD, Pratt WB. Folding of the glucocorticoid receptor by the reconstituted Hsp90-based chaperone machinery. The initial hsp90.p60.hsp70-dependent step is sufficient for creating the steroid binding conformation. J Biol Chem 272: 13047–13054, 1997.[Abstract/Free Full Text]
42. Dolinsky VW, Douglas DN, Lehner R, Vance DE. Regulation of the enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid dexamethasone. Biochem J 378: 967–974, 2004.[CrossRef][Web of Science][Medline]
43. Drake AJ, Livingstone DE, Andrew R, Seckl JR, Morton NM, Walker BR. Reduced adipose glucocorticoid reactivation and increased hepatic glucocorticoid clearance as an early adaptation to high-fat feeding in Wistar rats. Endocrinology 146: 913–919, 2005.[Abstract/Free Full Text]
44. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 53: 58–68, 1981.[Abstract/Free Full Text]
45. Emptoz-Bonneton A, Cousin P, Seguchi K, Avvakumov GV, Bully C, Hammond GL, Pugeat M. Novel human corticosteroid-binding globulin variant with low cortisol-binding affinity. J Clin Endocrinol Metab 85: 361–367, 2000.[Abstract/Free Full Text]
46. Encio IJ, Detera-Wadleigh SD. The genomic structure of the human glucocorticoid receptor. J Biol Chem 266: 7182–7188, 1991.[Abstract/Free Full Text]
47. Ewart HS, Carroll R, Severson DL. Lipoprotein lipase activity in rat cardiomyocytes is stimulated by insulin and dexamethasone. Biochem J 327: 439–442, 1997.
48. Ewart HS, Severson DL. Insulin and dexamethasone stimulation of cardiac lipoprotein lipase activity involves the actin-based cytoskeleton. Biochem J 340: 485–490, 1999.
49. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25: 543–567, 2004.[Abstract/Free Full Text]
50. Ferguson GT, Irvin CG, Cherniack RM. Effect of corticosteroids on diaphragm function and biochemistry in the rabbit. Am Rev Respir Dis 141: 156–163, 1990.[Web of Science][Medline]
51. Fernandez-Real JM, Pugeat M, Grasa M, Broch M, Vendrell J, Brun J, Ricart W. Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. J Clin Endocrinol Metab 87: 4686–4690, 2002.[Abstract/Free Full Text]
52. Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP. A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes. Cell Metab 1: 133–144, 2005.[CrossRef][Web of Science][Medline]
53. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109: 121–130, 2002.[CrossRef][Web of Science][Medline]
54. Firdaus M. Prevention and treatment of the metabolic syndrome in the elderly. J Okla State Med Assoc 98: 63–66, 2005.[Medline]
55. Fonarow GC. An approach to heart failure and diabetes mellitus. Am J Cardiol 96: 47E–52E, 2005.[Web of Science][Medline]
56. Francke U, Foellmer BE. The glucocorticoid receptor gene is in 5q31-q32 [corrected]. Genomics 4: 610–612, 1989.[CrossRef][Web of Science][Medline]
57. Freedman MR, Stern JS, Reaven GM, Mondon CE. Effect of adrenalectomy on in vivo glucose metabolism in insulin resistant Zucker obese rats. Horm Metab Res 18: 296–298, 1986.[Web of Science][Medline]
58. Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest 92: 2191–2198, 1993.[Web of Science][Medline]
59. Friedman JE, Yun JS, Patel YM, McGrane MM, Hanson RW. Glucocorticoids regulate the induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes. J Biol Chem 268: 12952–12957, 1993.[Abstract/Free Full Text]
60. Furuyama T, Kitayama K, Yamashita H, Mori N. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK-4 gene expression in skeletal muscle during energy deprivation. Biochem J 375: 365–371, 2003.[CrossRef][Web of Science][Medline]
61. Garfield SA, Scott AC, Cardell RR Jr. Alterations in hepatic fine structure after chronic exposure of rats to dexamethasone. Anat Rec 192: 73–87, 1978.[CrossRef][Medline]
62. Giorgino F, Almahfouz A, Goodyear LJ, Smith RJ. Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. J Clin Invest 91: 2020–2030, 1993.[Web of Science][Medline]
63. Golfman LS, Takeda N, Dhalla NS. Cardiac membrane Ca(2+)-transport in alloxan-induced diabetes in rats. Diabetes Res Clin Pract 31, Suppl: S73–S77, 1996.
64. Grasa MM, Cabot C, Balada F, Virgili J, Sanchis D, Monserrat C, Fernandez-Lopez JA, Remesar X, Alemany M. Corticosterone binding to tissues of adrenalectomized lean and obese Zucker rats. Horm Metab Res 30: 699–704, 1998.[Web of Science][Medline]
65. Grundy SM. Metabolic syndrome: therapeutic considerations. Handb Exp Pharmacol 170: 107–133, 2005.
66. Guillaume-Gentil C, Assimacopoulos-Jeannet F, Jeanrenaud B. Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats. Diabetologia 36: 899–906, 1993.[CrossRef][Web of Science][Medline]
67. Haber RS, Weinstein SP. Role of glucose transporters in glucocorticoid-induced insulin resistance. GLUT4 isoform in rat skeletal muscle is not decreased by dexamethasone. Diabetes 41: 728–735, 1992.[Abstract]
68. Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourg FP, Plumier JC, Rebsamen MC, Hsieh CM, Chui DS, Thomas KL, Prorock AJ, Laubach VE, Moskowitz MA, French BA, Ley K, Liao JK. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8: 473–479, 2002.[CrossRef][Web of Science][Medline]
69. Halleux CM, Takahashi M, Delporte ML, Detry R, Funahashi T, Matsuzawa Y, Brichard SM. Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue. Biochem Biophys Res Commun 288: 1102–1107, 2001.[CrossRef][Web of Science][Medline]
70. Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Le Grand CB, Li Z, Metzger JM, Mundt SS, Noonan H, Nunes CN, Olson SH, Pikounis B, Ren N, Robertson N, Schaeffer JM, Shah K, Springer MS, Strack AM, Strowski M, Wu K, Wu T, Xiao J, Zhang BB, Wright SD, Thieringer R. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 202: 517–527, 2005.[Abstract/Free Full Text]
71. Hollenberg AN, Susulic VS, Madura JP, Zhang B, Moller DE, Tontonoz P, Sarraf P, Spiegelman BM, Lowell BB. Functional antagonism between CCAAT/Enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma on the leptin promoter. J Biol Chem 272: 5283–5290, 1997.[Abstract/Free Full Text]
72. Holm C, Kirchgessner TG, Svenson KL, Fredrikson G, Nilsson S, Miller CG, Shively JE, Heinzmann C, Sparkes RS, Mohandas T, et al. Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q133. Science 241: 1503–1506, 1988.[Abstract/Free Full Text]
73. Holness MJ, Sugden MC. Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 31: 1143–1151, 2003.[Web of Science][Medline]
74. Huang B, Wu P, Bowker-Kinley MM, Harris RA. Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51: 276–283, 2002.[Abstract/Free Full Text]
75. Huang B, Wu P, Popov KM, Harris RA. Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney. Diabetes 52: 1371–1376, 2003.[Abstract/Free Full Text]
76. Hunger-Dathe W, Mosebach N, Samann A, Wolf G, Muller UA. Prevalence of impaired glucose tolerance 6 years after gestational diabetes. Exp Clin Endocrinol Diabetes 114: 11–17, 2006.[CrossRef][Web of Science][Medline]
77. Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 110: 1251–1257, 2004.
78. Ibrahim A, Natrajan S, Ghafoorunissa R. Dietary trans-fatty acids alter adipocyte plasma membrane fatty acid composition and insulin sensitivity in rats. Metabolism 54: 240–246, 2005.[CrossRef][Web of Science][Medline]
79. Jacobson PB, von Geldern TW, Ohman L, Osterland M, Wang J, Zinker B, Wilcox D, Nguyen PT, Mika A, Fung S, Fey T, Goos-Nilsson A, Grynfarb M, Barkhem T, Marsh K, Beno DW, Nga-Nguyen B, Kym PR, Link JT, Tu N, Edgerton DS, Cherrington A, Efendic S, Lane BC, Opgenorth TJ. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes. J Pharmacol Exp Ther 314: 191–200, 2005.[Abstract/Free Full Text]
80. Jamieson PM, Chapman KE, Edwards CR, Seckl JR. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology 136: 4754–4761, 1995.[Abstract]
81. Jeukendrup AE. Regulation of fat metabolism in skeletal muscle. Ann NY Acad Sci 967: 217–235, 2002.[Web of Science][Medline]
82. Joyner JM, Hutley LJ, Bachmann AW, Torpy DJ, Prins JB. Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency. Am J Physiol Endocrinol Metab 284: E1049–E1054, 2003.[Abstract/Free Full Text]
83. Kageyama H, Hirano T, Okada K, Ebara T, Kageyama A, Murakami T, Shioda S, Adachi M. Lipoprotein lipase mRNA in white adipose tissue but not in skeletal muscle is increased by pioglitazone through PPAR-gamma. Biochem Biophys Res Commun 305: 22–27, 2003.[CrossRef][Web of Science][Medline]
84. Kallen CB, Lazar MA. Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 93: 5793–5796, 1996.[Abstract/Free Full Text]
85. Kannisto K, Pietilainen KH, Ehrenborg E, Rissanen A, Kaprio J, Hamsten A, Yki-Jarvinen H. Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. J Clin Endocrinol Metab 89: 4414–4421, 2004.[Abstract/Free Full Text]
86. Kershaw EE, Morton NM, Dhillon H, Ramage L, Seckl JR, Flier JS. Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity. Diabetes 54: 1023–1031, 2005.[Abstract/Free Full Text]
87. Kidani T, Sakayama K, Masuno H, Takubo N, Matsuda Y, Okuda H, Yamamoto H. Active-dimeric form of lipoprotein lipase increases in the adipose tissue of patients with rheumatoid arthritis treated with prednisolone. Biochim Biophys Acta 1584: 31–36, 2002.[Medline]
88. Komamura K, Shirotani-Ikejima H, Tatsumi R, Tsujita-Kuroda Y, Kitakaze M, Miyatake K, Sunagawa K, Miyata T. Differential gene expression in the rat skeletal and heart muscle in glucocorticoid-induced myopathy: analysis by microarray. Cardiovasc Drugs Ther 17: 303–310, 2003.[CrossRef][Web of Science][Medline]
89. Kusunoki M, Cooney GJ, Hara T, Storlien LH. Amelioration of high-fat feeding-induced insulin resistance in skeletal muscle with the antiglucocorticoid RU486. Diabetes 44: 718–720, 1995.[Abstract]
90. Kwon HS, Huang B, Unterman TG, Harris RA. Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Diabetes 53: 899–910, 2004.[Abstract/Free Full Text]
91. Lankester DL, Brown AM, Zammit VA. Use of cytosolic triacylglycerol hydrolysis products and of exogenous fatty acid for the synthesis of triacylglycerol secreted by cultured rat hepatocytes. J Lipid Res 39: 1889–1895, 1998.[Abstract/Free Full Text]
92. Leckie C, Chapman KE, Edwards CR, Seckl JR. LLC-PK1 cells model 11 beta-hydroxysteroid dehydrogenase type 2 regulation of glucocorticoid access to renal mineralocorticoid receptors. Endocrinology 136: 5561–5569, 1995.[Abstract]
93. Lee HC, Lu T, Weintraub NL, VanRollins M, Spector AA, Shibata EF. Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes. J Physiol 519 (Pt 1): 153–168, 1999.
94. Lehner R, Verger R. Purification and characterization of a porcine liver microsomal triacylglycerol hydrolase. Biochemistry 36: 1861–1868, 1997.[CrossRef][Medline]
95. Lemberger T, Staels B, Saladin R, Desvergne B, Auwerx J, Wahli W. Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids. J Biol Chem 269: 24527–24530, 1994.[Abstract/Free Full Text]
96. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure. J Mol Cell Cardiol 33: 1065–1089, 2001.[CrossRef][Web of Science][Medline]
97. Liang Y, Osborne MC, Monia BP, Bhanot S, Watts LM, She P, DeCarlo SO, Chen X, Demarest K. Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice. Metabolism 54: 848–855, 2005.[CrossRef][Web of Science][Medline]
98. Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE, Permana PA, Tataranni PA, Walker BR. Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. J Clin Endocrinol Metab 88: 2738–2744, 2003.[Abstract/Free Full Text]
99. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 100: 3077–3082, 2003.[Abstract/Free Full Text]
100. Lister K, Autelitano DJ, Jenkins A, Hannan RD, Sheppard KE. Cross talk between corticosteroids and alpha-adrenergic signalling augments cardiomyocyte hypertrophy: a possible role for SGK1. Cardiovasc Res 70: 555–565, 2006.[Abstract/Free Full Text]
101. Liu Y, Nakagawa Y, Wang Y, Li R, Li X, Ohzeki T, Friedman TC. Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes 52: 1409–1416, 2003.[Abstract/Free Full Text]
102. Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 141: 560–563, 2000.[Abstract/Free Full Text]
103. Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 141: 560–563, 2000.[Abstract/Free Full Text]
104. Livingstone DE, Walker BR. Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats. J Pharmacol Exp Ther 305: 167–172, 2003.[Abstract/Free Full Text]
105. Lonnroth P, Smith U. The antilipolytic effect of insulin in human adipocytes requires activation of the phosphodiesterase. Biochem Biophys Res Commun 141: 1157–1161, 1986.[CrossRef][Web of Science][Medline]
106. Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1213: 263–276, 1994.[Medline]
107. Lowenberg M, Tuynman J, Scheffer M, Verhaar A, Vermeulen L, van Deventer S, Hommes D, Peppelenbosch M. Kinome analysis reveals nongenomic glucocorticoid receptor-dependent inhibition of insulin signaling. Endocrinology 147: 3555–3562, 2006.[Abstract/Free Full Text]
108. Ma K, Zhang Y, Elam MB, Cook GA, Park EA. Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor gamma coactivator. J Biol Chem 280: 29525–29532, 2005.[Abstract/Free Full Text]
109. Manger K, Kusus M, Forster C, Ropers D, Daniel WG, Kalden JR, Achenbach S, Manger B. Factors associated with coronary artery calcification in young female patients with SLE. Ann Rheum Dis 62: 846–850, 2003.[Abstract/Free Full Text]
110. Maser E, Volker B, Friebertshauser J. 11 Beta-hydroxysteroid dehydrogenase type 1 from human liver: dimerization and enzyme cooperativity support its postulated role as glucocorticoid reductase. Biochemistry 41: 2459–2465, 2002.[CrossRef][Medline]
111. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A transgenic model of visceral obesity and the metabolic syndrome. Science 294: 2166–2170, 2001.[Abstract/Free Full Text]
112. Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, regulation. J Lipid Res 43: 1997–2006, 2002.[Abstract/Free Full Text]
113. Mitsuya N, Kishi R, Suzuki N, Tamura M, Imai Y, Tanaka O, Takagi A, Nakazawa K, Miyake F, Nobuoka S, Koike J. Efficacy of steroid therapy for pacing failure in a patient with chronic myocarditis. Intern Med 43: 213–217, 2004.[CrossRef][Web of Science][Medline]
114. Morton NM, Holmes MC, Fievet C, Staels B, Tailleux A, Mullins JJ, Seckl JR. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 276: 41293–41300, 2001.[Abstract/Free Full Text]
115. Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 53: 931–938, 2004.[Abstract/Free Full Text]
116. Moyer ML, Borror KC, Bona BJ, DeFranco DB, Nordeen SK. Modulation of cell signaling pathways can enhance or impair glucocorticoid-induced gene expression without altering the state of receptor phosphorylation. J Biol Chem 268: 22933–22940, 1993.[Abstract/Free Full Text]
117. Oda N, Nakai A, Mokuno T, Sawai Y, Nishida Y, Mano T, Asano K, Itoh Y, Kotake M, Kato S. Dexamethasone-induced changes in glucose transporter 4 in rat heart muscle, skeletal muscle and adipocytes. Eur J Endocrinol 133: 121–126, 1995.[Abstract/Free Full Text]
118. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122: 707–721, 2005.[CrossRef][Web of Science][Medline]
119. Ogura M, Kusaka I, Nagasaka S, Yatagai T, Shinozaki S, Itabashi N, Nakamura T, Yokoyama M, Ishikawa SE, Ishibashi S. Unilateral adrenalectomy improves insulin resistance and diabetes mellitus in a patient with ACTH-independent macronodular adrenal hyperplasia. Endocr J 50: 715–721, 2003.[CrossRef][Web of Science][Medline]
120. Oliver JD, Rogers MP. Stimulation of lipoprotein lipase synthesis by refeeding, insulin and dexamethasone. Biochem J 292: 525–530, 1993.
121. Ong JM, Simsolo RB, Saffari B, Kern PA. The regulation of lipoprotein lipase gene expression by dexamethasone in isolated rat adipocytes. Endocrinology 130: 2310–2316, 1992.[Abstract/Free Full Text]
122. Opherk C, Tronche F, Kellendonk C, Kohlmuller D, Schulze A, Schmid W, Schutz G. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus. Mol Endocrinol 18: 1346–1353, 2004.[Abstract/Free Full Text]
123. Opie LH. Cardiac metabolism—emergence, decline, resurgence. Part I. Cardiovasc Res 26: 721–733, 1992.[Free Full Text]
124. Opie LH. Cardiac metabolism—emergence, decline, resurgence. Part II. Cardiovasc Res 26: 817–830, 1992.[Free Full Text]
125. Ousova O, Guyonnet-Duperat V, Iannuccelli N, Bidanel JP, Milan D, Genet C, Llamas B, Yerle M, Gellin J, Chardon P, Emptoz-Bonneton A, Pugeat M, Mormede P, Moisan MP. Corticosteroid binding globulin: a new target for cortisol-driven obesity. Mol Endocrinol 18: 1687–1696, 2004.[Abstract/Free Full Text]
126. Paterson JM, Morton NM, Fievet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR, Mullins JJ. Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA 101: 7088–7093, 2004.[Abstract/Free Full Text]
127. Paulson DJ, Crass MF 3rd. Endogenous triacylglycerol metabolism in diabetic heart. Am J Physiol Heart Circ Physiol 242: H1084–H1094, 1982.[Abstract/Free Full Text]
128. Pepe S. Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes. Exp Gerontol 40: 369–376, 2005.[CrossRef][Web of Science][Medline]
129. Phillips DI, Barker DJ, Fall CH, Seckl JR, Whorwood CB, Wood PJ, Walker BR. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 83: 757–760, 1998.[Abstract/Free Full Text]
130. Pompeia C, Freitas JJ, Kim JS, Zyngier SB, Curi R. Arachidonic acid cytotoxicity in leukocytes: implications of oxidative stress and eicosanoid synthesis. Biol Cell 94: 251–265, 2002.[CrossRef][Web of Science][Medline]
131. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 98: 596–605, 2006.[Abstract/Free Full Text]
132. Power RF, Mani SK, Codina J, Conneely OM, O'Malley BW. Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 254: 1636–1639, 1991.[Abstract/Free Full Text]
133. Pulinilkunnil T, Rodrigues B. Cardiac lipoprotein lipase: metabolic basis for diabetic heart disease. Cardiovasc Res 69: 329–340, 2006.[Abstract/Free Full Text]
134. Qi D, An D, Kewalramani G, Qi Y, Pulinilkunnil T, Abrahani A, Al-Altar U, Ghosh S, Wambolt RB, Allard MF, Innis SM, Rodrigues B. Altered cardiac fatty acid composition and utilization following dexamethasone induced insulin resistance. Am J Physiol Endocrinol Metab 291: E420–E427, 2006.[Abstract/Free Full Text]
135. Qi D, Pulinilkunnil T, An D, Ghosh S, Abrahani A, Pospisilik JA, Brownsey R, Wambolt R, Allard M, Rodrigues B. Single-dose dexamethasone induces whole-body insulin resistance and alters both cardiac fatty acid and carbohydrate metabolism. Diabetes 53: 1790–1797, 2004.[Abstract/Free Full Text]
136. Raff H, Bruder ED. Adiponectin and resistin in the neonatal rat: effects of dexamethasone and hypoxia. Endocrine 29: 341–344, 2006.[CrossRef][Web of Science][Medline]
137. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785–789, 1963.[Web of Science][Medline]
138. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86: 1418–1421, 2001.[Abstract/Free Full Text]
139. Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, Johnson O, Andrew R, Olsson T. Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87: 3330–3336, 2002.[Abstract/Free Full Text]
140. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 1595–1607, 1988.[Abstract]
141. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med 353: 1711–1723, 2005.[Free Full Text]
142. Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM. Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues. J Clin Endocrinol Metab 83: 1325–1335, 1998.[Abstract/Free Full Text]
143. Ritz P, Dumas JF, Ducluzeau PH, Simard G. Hormonal regulation of mitochondrial energy production. Curr Opin Clin Nutr Metab Care 8: 415–418, 2005.[Web of Science][Medline]
144. Rizzo MT, Regazzi E, Garau D, Akard L, Dugan M, Boswell HS, Rizzoli V, Carlo-Stella C. Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells. Cancer Res 59: 5047–5053, 1999.[Abstract/Free Full Text]
145. Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol 27: 169–179, 1995.[Web of Science][Medline]
146. Rodrigues B, Goyal RK, McNeill JH. Effects of hydralazine on streptozotocin-induced diabetic rats: prevention of hyperlipidemia and improvement in cardiac function. J Pharmacol Exp Ther 237: 292–299, 1986.[Abstract/Free Full Text]
147. Rodrigues B, McNeill JH. Cardiac function in spontaneously hypertensive diabetic rats. Am J Physiol Heart Circ Physiol 251: H571–H580, 1986.[Abstract/Free Full Text]
148. Rodrigues B, McNeill JH. The diabetic heart: metabolic causes for the development of a cardiomyopathy. Cardiovasc Res 26: 913–922, 1992.[Web of Science][Medline]
149. Rosmond R. The glucocorticoid receptor gene and its association to metabolic syndrome. Obes Res 10: 1078–1086, 2002.[Web of Science][Medline]
150. Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab 83: 1853–1859, 1998.[Abstract/Free Full Text]
151. Ruzzin J, Wagman AS, Jensen J. Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor. Diabetologia 48: 2119–2130, 2005.[CrossRef][Web of Science][Medline]
152. Saddik M, Lopaschuk GD. Triacylglycerol turnover in isolated working hearts of acutely diabetic rats. Can J Physiol Pharmacol 72: 1110–1119, 1994.[Web of Science][Medline]
153. Saether T, Tran TN, Rootwelt H, Christophersen BO, Haugen TB. Expression and regulation of delta5-desaturase, delta6-desaturase, stearoyl-coenzyme A (CoA) desaturase 1, and stearoyl-CoA desaturase 2 in rat testis. Biol Reprod 69: 117–124, 2003.[Abstract/Free Full Text]
154. Saito F, Kawaguchi M, Izumida J, Asakura T, Maehara K, Maruyama Y. Alteration in haemodynamics and pathological changes in the cardiovascular system during the development of Type 2 diabetes mellitus in OLETF rats. Diabetologia 46: 1161–1169, 2003.[CrossRef][Web of Science][Medline]
155. Saklatvala J. Glucocorticoids: do we know how they work? Arthritis Res 4: 146–150, 2002.[CrossRef][Web of Science][Medline]
156. Sakoda H, Ogihara T, Anai M, Funaki M, Inukai K, Katagiri H, Fukushima Y, Onishi Y, Ono H, Fujishiro M, Kikuchi M, Oka Y, Asano T. Dexamethasone-induced insulin resistance in 3T3–L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction. Diabetes 49: 1700–1708, 2000.[Abstract]
157. Saxena U, Klein MG, Goldberg IJ. Transport of lipoprotein lipase across endothelial cells. Proc Natl Acad Sci USA 88: 2254–2258, 1991.[Abstract/Free Full Text]
158. Saxon ME, Filippov AK, Porotikov UI. The possible role of phospholipase A2 in cardiac membrane destabilization under calcium overload conditions. Basic Res Cardiol 79: 668–678, 1984.[CrossRef][Web of Science][Medline]
159. Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96: 23–43, 2002.[CrossRef][Web of Science][Medline]
160. Scorrano L, Penzo D, Petronilli V, Pagano F, Bernardi P. Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling. J Biol Chem 276: 12035–12040, 2001.[Abstract/Free Full Text]
161. Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action. Endocrinology 142: 1371–1376, 2001.[Abstract/Free Full Text]
162. Selyatitskaya VG, Kuz'minova OI, Odintsov SV. Development of insulin resistance in experimental animals during long-term glucocorticoid treatment. Bull Exp Biol Med 133: 339–341, 2002.[CrossRef][Web of Science][Medline]
163. Severino C, Brizzi P, Solinas A, Secchi G, Maioli M, Tonolo G. Low-dose dexamethasone in the rat: a model to study insulin resistance. Am J Physiol Endocrinol Metab 283: E367–E373, 2002.[Abstract/Free Full Text]
164. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH, Taegtmeyer H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18: 1692–1700, 2004.[Abstract/Free Full Text]
165. Slavin BG, Ong JM, Kern PA. Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes. J Lipid Res 35: 1535–1541, 1994.[Abstract]
166. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV Jr. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 25: 87–90, 2000.[CrossRef][Web of Science][Medline]
167. Stewart PM. Krozowski-Hydroxysteroid dehydrogenase. Vitam Horm 57: 249–324, 1999.[Web of Science][Medline]
168. Stins MF, Maxfield FR, Goldberg IJ. Polarized binding of lipoprotein lipase to endothelial cells. Implications for its physiological actions. Arterioscler Thromb 12: 1437–1446, 1992.[Abstract/Free Full Text]
169. Stojanovska L, Rosella G, Proietto J. Evolution of dexamethasone-induced insulin resistance in rats. Am J Physiol Endocrinol Metab 258: E748–E756, 1990.[Abstract/Free Full Text]
170. Stolk RP, Lamberts SW, de Jong FH, Pols HA, Grobbee DE. Gender differences in the associations between cortisol and insulin in healthy subjects. J Endocrinol 149: 313–318, 1996.[Abstract/Free Full Text]
171. Stone NJ, Saxon D. Approach to treatment of the patient with metabolic syndrome: lifestyle therapy. Am J Cardiol 96: 15E–21E, 2005.[Web of Science][Medline]
172. Sul HS, Wang D. Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu Rev Nutr 18: 331–351, 1998.[CrossRef][Web of Science][Medline]
173. Tahiliani AG, McNeill JH. Diabetes-induced abnormalities in the myocardium. Life Sci 38: 959–974, 1986.[CrossRef][Web of Science][Medline]
174. Thiemermann C. Corticosteroids and cardioprotection. Nat Med 8: 453–455, 2002.[CrossRef][Web of Science][Medline]
175. Thomas CR, Turner SL, Jefferson WH, Bailey CJ. Prevention of dexamethasone-induced insulin resistance by metformin. Biochem Pharmacol 56: 1145–1150, 1998.[CrossRef][Web of Science][Medline]
176. Tomlinson JW, Moore JS, Clark PM, Holder G, Shakespeare L, Stewart PM. Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue. J Clin Endocrinol Metab 89: 2711–2716, 2004.[Abstract/Free Full Text]
177. Tomlinson JW, Sinha B, Bujalska I, Hewison M, Stewart PM. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J Clin Endocrinol Metab 87: 5630–5635, 2002.[Abstract/Free Full Text]
178. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8: 1224–1234, 1994.[Abstract/Free Full Text]
179. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8: 1224–1234, 1994.[Abstract/Free Full Text]
180. Torpy DJ, Bachmann AW, Grice JE, Fitzgerald SP, Phillips PJ, Whitworth JA, Jackson RV. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab 86: 3692–3700, 2001.[Abstract/Free Full Text]
181. Turnbow MA, Keller SR, Rice KM, Garner CW. Dexamethasone down-regulation of insulin receptor substrate-1 in 3T3-L1 adipocytes. J Biol Chem 269: 2516–2520, 1994.[Abstract/Free Full Text]
182. van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res 45: 279–293, 2000.[Abstract/Free Full Text]
183. Venkatesan N, Lim J, Bouch C, Marciano D, Davidson MB. Dexamethasone-induced impairment in skeletal muscle glucose transport is not reversed by inhibition of free fatty acid oxidation. Metabolism 45: 92–100, 1996.[CrossRef][Web of Science][Medline]
184. Verrier E, Wang L, Wadham C, Albanese N, Hahn C, Gamble JR, Chatterjee VK, Vadas MA, Xia P. PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase. Circ Res 94: 1515–1522, 2004.[Abstract/Free Full Text]
185. Viengchareun S, Zennaro MC, Pascual-Le Tallec L., Lombes M. Brown adipocytes are novel sites of expression and regulation of adiponectin and resistin. FEBS Lett 532: 345–350, 2002.[CrossRef][Web of Science][Medline]
186. Vikramadithyan RK, Hirata K, Yagyu H, Hu Y, Augustus A, Homma S, Goldberg IJ. Peroxisome proliferator-activated receptor agonists modulate heart function in transgenic mice with lipotoxic cardiomyopathy. J Pharmacol Exp Ther 313: 586–593, 2005.[Abstract/Free Full Text]
187. Vlachoyiannopoulos PG, Kanellopoulos PG, Ioannidis JP, Tektonidou MG, Mastorakou I, Moutsopoulos HM. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology (Oxf) 42: 645–651, 2003.
188. Walker BR, Campbell JC, Fraser R, Stewart PM, Edwards CR. Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf) 37: 483–492, 1992.[Medline]
189. Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CR. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab 80: 3155–3159, 1995.[Abstract]
190. Wang M. The role of glucocorticoid action in the pathophysiology of the metabolic syndrome. Nutr Metab (Lond) 2: 3, 2005.
191. Wang Y, Jones Voy B, Urs S, Kim S, Soltani-Bejnood M, Quigley N, Heo YR, Standridge M, Andersen B, Dhar M, Joshi R, Wortman P, Taylor JW, Chun J, Leuze M, Claycombe K, Saxton AM, Moustaid-Moussa N. The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr 134: 1032–1038, 2004.[Abstract/Free Full Text]
192. Weaver JU, Hitman GA, Kopelman PG. An association between a Bc1I restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia in obese women. J Mol Endocrinol 9: 295–300, 1992.[Abstract/Free Full Text]
193. Weigel NL, Zhang Y. Ligand-independent activation of steroid hormone receptors. J Mol Med 76: 469–479, 1998.[CrossRef][Web of Science][Medline]
194. Weinstein SP, Wilson CM, Pritsker A, Cushman SW. Dexamethasone inhibits insulin-stimulated recruitment of GLUT4 to the cell surface in rat skeletal muscle. Metabolism 47: 3–6, 1998.[Web of Science][Medline]
195. Weiser JN, Do YS, Feldman D. Synthesis and secretion of corticosteroid-binding globulin by rat liver. A source of heterogeneity of hepatic corticosteroid-binders. J Clin Invest 63: 461–467, 1979.[Web of Science][Medline]
196. Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 51: 1066–1075, 2002.[Abstract/Free Full Text]
197. Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 51: 1066–1075, 2002.[Abstract/Free Full Text]
198. Whorwood CB, Mason JI, Ricketts ML, Howie AJ, Stewart PM. Detection of human 11 beta-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase-polymerase chain reaction and localization of the type 2 isoform to renal collecting ducts. Mol Cell Endocrinol 110: R7–R12, 1995.[CrossRef][Web of Science][Medline]
199. Wiggins D, Gibbons GF. The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas. Biochem J 284: 457–462, 1992.
200. Witteles RM, Tang WH, Jamali AH, Chu JW, Reaven GM, Fowler MB. Insulin resistance in idiopathic dilated cardiomyopathy: a possible etiologic link. J Am Coll Cardiol 44: 78–81, 2004.[Abstract/Free Full Text]
201. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 111: 419–426, 2003.[CrossRef][Web of Science][Medline]
202. Young LH, Li J, Baron SJ, Russell RR. AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovasc Med 15: 110–118, 2005.[CrossRef][Web of Science][Medline]
203. Zecca E, Papacci P, Maggio L, Gallini F, Elia S, De Rosa G, Romagnoli C. Cardiac adverse effects of early dexamethasone treatment in preterm infants: a randomized clinical trial. J Clin Pharmacol 41: 1075–1081, 2001.[Abstract]
204. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97: 1784–1789, 2000.[Abstract/Free Full Text]
205. Zilberfarb V, Siquier K, Strosberg AD, Issad T. Effect of dexamethasone on adipocyte differentiation markers and tumour necrosis factor-alpha expression in human PAZ6 cells. Diabetologia 44: 377–386, 2001.[CrossRef][Web of Science][Medline]

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