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

Hepatic triacylglycerol secretion is elevated in insulin-resistant states. Microsomal diacylglycerol acyltransferase (DGAT) catalyzes the final reaction in the synthesis of triacylglycerol (TAG). We have previously described two DGAT activities in rat liver microsomes, one overt (cytosol-facing) and one latent (endoplasmic reticulum lumen-facing) (Owen MR, Corstorphine CG, Zammit VA: Overt and latent activities of diacylglycerol acytransferase in rat liver microsomes: possible roles in very-low-density lipoprotein triacylglycerol secretion. Biochem J 323:17-21, 1977). It was suggested that they are involved in the synthesis of TAG for the cytosolic droplet and VLDL lipidation, respectively. In the present study, we measured the overt and latent DGAT activities in rats fed diets containing one of two hypolipidemic drugs: fenofibrate (a peroxisome proliferator-activated receptor alpha [PPARalpha] agonist) and simvastatin (a 3-hydroxy-3-methylglutaryl [HMG]-CoA reductase inhibitor). We found that the activities of the two DGATs could be varied independently by these treatments. Fenofibrate raised overt DGAT activity but lowered that of latent DGAT. In contrast, simvastatin markedly lowered overt DGAT activity without affecting that of latent DGAT. The increase in overt DGAT activity induced by fenofibrate could not be mimicked by feeding a diet enriched in n-3 polyunsaturated fatty acids (PUFA), which lowered overt DGAT activity but did not affect latent DGAT, suggesting that n-3 PUFA act through a mechanism independent of PPARalpha activation. The fibrate-induced increase in overt DGAT activity and the inhibition of latent DGAT may provide a mechanism through which acyl moieties are retained within the liver for oxidation through the pathways concomitantly upregulated by PPARalpha activation.
Diabetes 2002 Jun
PMID:Differential effects of fenofibrate or simvastatin treatment of rats on hepatic microsomal overt and latent diacylglycerol acyltransferase activities. 1203 56

Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and atherosclerosis. We have recently demonstrated that exposure of rodents to potent PPs indirectly causes a number of immunomodulating effects, resulting in severe adaptive immunosuppression. Since the peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in mediating the pleiotropic responses exerted by PPs, we have compared here the immunomodulating effects of the PPs perfluorooctanoic acid (PFOA) and Wy-14,643 in wild-type and PPARalpha-null mice. The reductions in spleen weight and in the number of splenocytes caused by PP treatment in wild-type mice was not observed in PPARalpha-null mice. Furthermore, the reductions in thymus weight and in the number of thymocytes were potently attenuated in the latter animals. Similarly, the dramatic decreases in the size of the CD4(+)CD8(+) population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of the cell cycle observed in wild-type mice administered PPs were much less extensive in PPARalpha-null mice. Finally, in contrast to the case of wild-type animals, the response of splenocytes isolated from the spleen of PP-treated PPARalpha-null mice to appropriate T- or B-cell activators in vitro was not reduced. Altogether, these data indicate that PPARalpha plays a major role in the immunomodulation caused by PPs. The possible relevance of these changes to the alterations in plasma lipids also caused by PPs is discussed.
 ...
PMID:Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice. 1203 74

The tremendous energy demands of the post-natal mammalian heart are fulfilled via dynamic flux through mitochondrial oxidative pathways. The capacity for energy production via fatty acid (FA) beta-oxidation pathway is determined, in part, by the regulated expression of genes encoding FA utilization enzymes and varies in accordance with diverse dietary and physiologic conditions. For example, fasting and diabetes activate the expression of cardiac FA oxidation (FAO). Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor that is known to control the expression of many genes involved in cellular FA import and oxidation. Cardiac FA utilization rates are reduced in PPARalpha null mice due to diminished expression of genes encoding FAO enzymes. Recent work has shown that the PPARalpha regulatory pathway is deactivated in pathologic cardiac hypertrophy and hypoxia, two circumstances characterized by reduced FAO and increased dependence on glucose as a fuel source. Conversely, the activity of the PPARalpha gene regulatory pathway is increased in the diabetic heart, which relies primarily on FAO for energy production. In fact, evidence is emerging that excessive FA import and oxidation may be a cause of pathologic cardiac remodeling in the diabetic heart. This review summarizes the regulation of cardiac substrate utilization pathways via the PPARalpha complex in the normal and diseased heart.
 ...
PMID:Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart. 1242 23

To explore the role of peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPARalpha deficiency (PPARalpha(-/-)) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPARalpha(-/-) mice were protected from the development of diabetes-induced cardiac hypertrophy, the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype than either did alone. Cardiomyopathy in diabetic MHC-PPAR mice was accompanied by myocardial long-chain triglyceride accumulation. The cardiomyopathic phenotype was exacerbated in MHC-PPAR mice fed a diet enriched in triglyceride containing long-chain fatty acid, an effect that was reversed by discontinuing the high-fat diet and absent in mice given a medium-chain triglyceride-enriched diet. Reactive oxygen intermediates were identified as candidate mediators of cardiomyopathic effects in MHC-PPAR mice. These results link dysregulation of the PPARalpha gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy.
 ...
PMID:A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. 1255 26

2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220) was newly synthesized and demonstrated to be a novel potent peroxisome proliferator-activated receptor alpha (PPARalpha) agonist with high subtype selectivity. In cell-based reporter gene assays, the EC(50) values of NS-220 for human PPARalpha, PPARgamma, and PPARdelta were 1.9 x 10(-8), 9.6 x 10(-6), and >10(-4) M, respectively, and for mouse PPARalpha, PPARgamma, and PPARdelta were 5.5 x 10(-8), 3.3 x 10(-5), and >10(-4) M, respectively. In addition, [(3)H]NS-220 bound to the ligand-binding domain of human PPARalpha with a K(D) value of 1.85 x 10(-7) M. Fenofibric acid and bezafibrate showed weak agonist activity for PPARalpha (EC(50), 2-8 x 10(-5) M), with poor subtype selectivity. NS-220 (0.1-3 mg/kg p.o.) decreased plasma triglyceride levels in ddY mice in a dose-dependent manner, but its hypolipidemic activity was abolished in PPARalpha-deficient mice. In KK-A(y) mice, an animal model of type-2 diabetes, NS-220 (0.3-1 mg/kg p.o.; 4 days) and fenofibrate (100-300 mg/kg p.o.; 4 days) decreased plasma triglyceride and glucose levels in a dose-dependent manner. In a 2-week repeated administration test, NS-220 (0.3-1 mg/kg p.o.) decreased plasma glucose levels markedly without increasing in plasma insulin levels. Furthermore, NS-220 increased high-density lipoprotein levels and decreased triglyceride-rich lipoprotein levels. In conclusion, a newly synthesized dioxanecarboxylic acid derivative, NS-220, is a potent and highly selective PPARalpha agonist that ameliorates metabolic disorders in diabetic mice. These results strongly suggest that it will be a promising drug for the treatment of hyperlipidemia or metabolic disorders in type-2 diabetes.
 ...
PMID:A novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-Ay mice. 1498 65

In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non-ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non-ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non-ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) -regulated genes, myosin heavy chain beta (MHC-beta), and tumor necrosis factor alpha (TNF-alpha). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.
 ...
PMID:Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. 1552 14

Type 2 diabetes is an important cardiovascular risk factor. A significant component of the risk associated with type 2 diabetes is thought to be because of its characteristic lipid "triad" profile of raised small dense low-density lipoprotein levels, lowered high-density lipoprotein, and elevated triglycerides (TGs). Trials of statins and fibrates have included substantial numbers of patients with diabetes and indicate that lipid lowering reduces cardiovascular event rates in these patients. However, statins alone do not always address all the lipid abnormalities of diabetes. Fibrates, which have low affinity for peroxisome proliferator-activated receptor alpha (PPARalpha), improve most aspects of the atherogenic dyslipidemia of diabetes. Chronic elevations of free fatty acids (FFA) induce insulin resistance and contribute to the lipid triad of diabetes. Therefore, reducing their levels is likely to ameliorate insulin resistance and improve the lipid triad of diabetes. PPARs are intimately involved in the regulation of FFA: PPARalpha modulation increases FFA catabolism and PPARgamma agonism (eg, by thiazolidinediones) increases TG lipolysis, FFA transport, conversion of FFA to TGs, and safe storage of FFA. Integrating potent PPARalpha and PPARgamma activity may deliver greater improvement of the diabetic dyslipidemic profile and its attendant risks than selective PPAR activation.
 ...
PMID:Type 2 diabetes, dyslipidemia, and vascular risk: rationale and evidence for correcting the lipid imbalance. 1629 Sep 51

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the ligand-activated nuclear receptor superfamily, and plays an important role in lipid metabolism and glucose homeostasis. The purpose of this study is to determine whether the activation of PPARalpha by fenofbrate would improve diabetes and its renal complications in type II diabetes mellitus. Male C57 BLKS db/db mice and db/m controls at 8 weeks of age were divided to receive either a regular diet chow (db/db, n=8; db/m, n=6) or a diet containing fenofibrate (db/db, n=8; db/m, n=7). Mice were followed for 8 weeks. Fenofibrate treatment dramatically reduced fasting blood glucose (P<0.001) and HbA1c levels (P<0.001), and was associated with decreased food intake (P<0.01) and slightly reduced body weight. Fenofibrate also ameliorated insulin resistance (P<0.001) and reduced plasma insulin levels (P<0.05) in db/db mice. Hypertrophy of pancreatic islets was decreased and insulin content markedly increased (P<0.05) in fenofibrate-treated diabetic animals. In addition, fenofibrate treatment significantly reduced urinary albumin excretion (P<0.001). This was accompanied by dramatically reduced glomerular hypertrophy and mesangial matrix expansion. Furthermore, the addition of fenofibrate to cultured mesangial cells, which possess functional active PPARalpha, decreased type I collagen production. Taken together, the PPARalpha agonist fenofibrate dramatically improves hyperglycemia, insulin resistance, albuminuria, and glomerular lesions in db/db mice. The activation of PPARalpha by fenofibrate in mesangial cells may partially contribute to its renal protection. Thus, fenofibrate may serve as a therapeutic agent for type II diabetes and diabetic nephropathy.
 ...
PMID:PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. 1667 17

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice establish that PPARalpha was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Delta(5) desaturase (Delta(5)D), Delta(6)D, and Delta(9)D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Delta(5)D, Delta(6)D, and Delta(9)D. Only Delta(9)D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of l-type pyruvate kinase, Delta(9)D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Delta(9)D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lep(ob/ob)), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Delta(9)D expression and the massive accumulation of monounsaturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition.
 ...
PMID:Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. 1679 Aug 40

Physiological and pathophysiological conditions often affect the expression of drug metabolizing enzymes such as cytochromes P450 (P450s). Diabetes is one such factor and it is of great interest to understand its effects on drug metabolism, since diabetic patients generally have increased need for pharmacotherapy. We have recently reported the coordinated reduction of CYP2B1/2 and their transcriptional regulator constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, in the liver of genetically obese/diabetic Zucker fatty rats (Xiong, H., Yoshinari, K., et al., Drug Metab. Dispos., 30, 918-923, 2002). In this study, we investigated the expression of P450s and liver-enriched nuclear receptors in the liver of genetically diabetic db/db mice. Surprisingly, both CYP2B10 and CAR levels were increased in db/db mice. CYP4A expression was also increased at both mRNA and protein levels in db/db mice, while those of peroxisome proliferator-activated receptor alpha, a key regulator for the transcriptional activation of CYP4As, were comparable to those in age-matched C57BL/6 mice. Our results demonstrate that db/db mice and Zucker fatty rats exhibit different expression profiles of P450s and nuclear receptors despite their similar characteristics for obesity and diabetes resulting from a defect in the leptin signaling pathway.
 ...
PMID:Changes in the expression of cytochromes P450 and nuclear receptors in the liver of genetically diabetic db/db mice. 1688 Jun 18


<< Previous 1 2 3 4 5 6 7 Next >>