Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of nitric oxide (NO), regulates myocardial contractility. It is not known whether this effect is accompanied by a change in heart metabolism. We report here the effects of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), a cGMP analog, on regulatory steps of glucose metabolism in isolated working rat hearts perfused with glucose as the substrate. When glucose uptake was stimulated by increasing the workload, addition of the cGMP analog totally suppressed this stimulation and accelerated net glycogen breakdown. 8-BrcGMP did not affect pyruvate dehydrogenase activity but activated acetyl-CoA carboxylase, the enzyme that produces malonyl-CoA, an inhibitor of long-chain fatty acid oxidation. To test whether glucose metabolism could also be affected by altering the intracellular concentration of cGMP, we perfused hearts with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, or with S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. Perfusion with L-NAME decreased cGMP and increased glucose uptake by 30%, whereas perfusion with SNAP resulted in opposite effects. None of these conditions affected adenosine 3',5'-cyclic monophosphate concentration. Limitation of glucose uptake by SNAP or 8-BrcGMP decreased heart work, and this was reversed by adding alternative oxidizable substrates (pyruvate, beta-hydroxybutyrate) together with glucose. Therefore, increased NO production decreases myocardial glucose utilization and limits heart work. This effect is mediated by cGMP, which is thus endowed with both physiological and metabolic properties.
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PMID:Inhibition of myocardial glucose uptake by cGMP. 961 48

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.
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PMID:Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat. 1104 15

To test whether the acute reduction of nitric oxide (NO) synthesis causes changes in cardiac substrate metabolism and in the activity of key enzymes of fatty acid and glucose oxidation, we blocked NOS by giving N(omega)-nitro-L-arginine methyl ester (L-NAME; 35 mg/kg iv two times) to nine chronically instrumented dogs. [3H]oleate, [14C]glucose, and [13C]lactate were infused to measure the rate of cardiac substrate uptake and oxidation. Glyceraldehyde-3-phosphate dehydrogenase, acetyl-CoA carboxylase, and malonyl-CoA decarboxylase activities were measured in myocardial biopsies. In eight control dogs, ANG II was infused (20-40 ng x kg(-1) x min(-1)) to mimic the hemodynamic effects of L-NAME. After L-NAME, significant changes occurred for fatty acid oxidation (from 9.8 +/- 0.8 to 7.1 +/- 1.2 micromol/min), glucose uptake (from 12.9 +/- 5.5 to 45.0 +/- 14.2 micromol/min), and oxidation (from 4.4 +/- 1.2 to 19.9 +/- 2.3 micromol/min). ANG caused only a significantly lower increase in glucose oxidation. Lactate uptake increased by more than twofold in both groups. The enzyme activities did not differ significantly between the two groups. In conclusion, the acute inhibition of NO synthesis causes marked metabolic alterations that do not involve key rate-controlling enzymes of fatty acid oxidation nor glyceraldehyde-3-phosphate dehydrogenase.
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PMID:Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. 1173 1

The role of nitric oxide (NO)/guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathway in the regulation of fatty acid metabolism was investigated in rat hepatocytes. Treatment with NO donors, which are known to activate soluble guanylyl cyclase, inhibited in parallel fatty acid synthesis de novo and acetyl-CoA carboxylase activity. This effect was mimicked by 8-Br-cGMP and abolished by KT5823, a selective inhibitor of cGMP-dependent protein kinase (PKG). Furthermore, specific and hydrolysis-resistant activators of PKG, and inhibitors of Ca2+ release from endoplasmic reticulum, were also effective in inhibiting both fatty acid-synthesizing activities. These results suggest that this biological action of NO is regulated by a signaling cascade involving soluble guanylyl cyclase, cGMP, and PKG, and may be mediated, at least in part, by inhibition of Ca2+ release from endoplasmic reticulum. In addition, 8-Br-cGMP was able to stimulate fatty acid oxidation by two different mechanisms: the relieving of malonyl-CoA-dependent inhibition by lowering levels of this product of acetyl-CoA carboxylase, and a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I. Taken together, results of this study suggest that NO/cGMP signaling pathway is endowed with regulatory properties in fatty acid metabolism, and may have a physiological role in the control of this metabolism in liver.
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PMID:Involvement of nitric oxide/cyclic GMP signaling pathway in the regulation of fatty acid metabolism in rat hepatocytes. 1263 70

Globalization and global market have contributed to increased consumption of high-fat, energy-dense diets, particularly rich in saturated fatty acids( SFAs). Polyunsaturated fatty acids (PUFAs) regulate fuel partitioning within the cells by inducing their own oxidation through the reduction of lipogenic gene expression and the enhancement of the expression of those genes controlling lipid oxidation and thermogenesis. Moreover, PUFAs prevent insulin resistance by increasing membrane fluidity and GLUT4 transport. In contrast, SFAs are stored in non-adipocyte cells as triglycerides (TG) leading to cellular damage as a sequence of their lipotoxicity. Triglyceride accumulation in skeletal muscle cells (IMTG) derives from increased FA uptake coupled with deficient FA oxidation. High levels of circulating FAs enhance the expression of FA translocase the FA transport proteins within the myocites. The biochemical mechanisms responsible for lower fatty acid oxidation involve reduced carnitine palmitoyl transferase (CPT) activity, as a likely consequence of increased intracellular concentrations of malonyl-CoA; reduced glycogen synthase activity; and impairment of insulin signalling and glucose transport. The depletion of IMTG depots is strictly associated with an improvement of insulin sensitivity, via a reduced acetyl-CoA carboxylase (ACC) mRNA expression and an increased GLUT4 expression and pyruvate dehydrogenase (PDH) activity. In pancreatic islets, TG accumulation causes impairment of insulin secretion. In rat models, beta-cell dysfunction is related to increased triacylglycerol content in islets, increased production of nitric oxide, ceramide synthesis and beta-cell apoptosis. The decreased insulin gene promoter activity and binding of the pancreas-duodenum homeobox-1 (PDX-1) transcription factor to the insulin gene seem to mediate TG effect in islets. In humans, acute and prolonged effects of FAs on glucose-stimulated insulin secretion have been widely investigated as well as the effect of high-fat diets on insulin sensitivity and secretion and on the development of type 2 diabetes.
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PMID:Effects of dietary fatty acids on insulin sensitivity and secretion. 1547 16

The mechanisms by which ethanol causes accumulation of hepatic triacylglycerols are complex. It has been proposed that nitric oxide/cyclic GMP signaling pathway may be involved in regulation of fatty acid metabolism in the liver. Here, we investigated if this mechanism may have a role in adaptation to ethanol consumption. Hepatocytes were isolated from rats fed with an ethanol-containing liquid diet and pair-fed control rats, and incubated with a range of concentrations of 8-bromo-cyclic GMP. In both types of cells, this cyclic GMP analog inhibited in parallel fatty acid synthesis de novo and acetyl-CoA carboxylase activity. Addition of 8-bromo-cyclic GMP also decreased the rate of palmitate esterification to triacylglycerols and phospholipids, whereas palmitate oxidation was increased. However, in all these metabolic effects, hepatocytes from ethanol-fed rats were significantly less sensitive to the addition of 8-bromo-cyclic GMP. In order to know if this may be a more general mechanism of adaptation to ethanol, we also studied the effects on glucose metabolism. Similarly, hepatocytes from ethanol-fed rats showed a decreased sensitivity in the inhibition by 8-bromo-cyclic GMP of glycogen synthesis, fatty acid synthesis and the synthesis of glycerol backbone of hepatic triacylglycerols. These data suggest that ethanol consumption induces a desensitization of the regulatory effects mediated by cyclic GMP in fatty acid metabolism, contributing to triacylglycerol accumulation in the liver.
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PMID:Desensitization of cyclic GMP-mediated regulation of fatty acid metabolism in hepatocytes from ethanol-fed rats. 1561 22

Fenofibrate improves endothelial function by lipid-lowering and anti-inflammatory effects. Additionally, fenofibrate has been demonstrated to upregulate endothelial nitric oxide synthase (eNOS). AMP-activated protein kinase (AMPK) has been reported to phosphorylate eNOS at Ser-1177 and stimulate vascular endothelium-derived nitric oxide (NO) production. We report here that fenofibrate activates AMPK and increases eNOS phosphorylation and NO production in human umbilical vein endothelial cells (HUVEC). Incubation of HUVEC with fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase. Fenofibrate simultaneously increased eNOS phosphorylation and NO production. Inhibitors of protein kinase A and phosphatidylinositol 3-kinase failed to suppress the fenofibrate-induced eNOS phosphorylation. Neither bezafibrate nor WY-14643 activated AMPK in HUVEC. Furthermore, fenofibrate activated AMPK without requiring any transcriptional activities. These results indicate that fenofibrate stimulates eNOS phosphorylation and NO production through AMPK activation, which is suggested to be a novel characteristic of this agonist and unrelated to its effects on peroxisome proliferator-activated receptor alpha.
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PMID:Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC. 1644 96

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Nitric oxide (NO) and 5'-AMP-activated protein kinase (AMPK) are involved in glucose transport and mitochondrial biogenesis in skeletal muscle. Here, we examined whether NO regulates the expression of the major glucose transporter in muscle (GLUT4) and whether it influences AMPK-induced upregulation of GLUT4. At low levels, the NO donor S-nitroso-N-penicillamine (SNAP, 1 and 10 microM) significantly increased GLUT4 mRNA ( approximately 3-fold; P < 0.05) in L6 myotubes, and cotreatment with the AMPK inhibitor compound C ablated this effect. The cGMP analog 8-bromo-cGMP (8-Br-cGMP, 2 mM) increased GLUT4 mRNA by approximately 50% (P < 0.05). GLUT4 protein expression was elevated 40% by 2 days treatment with 8-Br-cGMP, whereas 6 days treatment with 10 microM SNAP increased GLUT4 expression by 65%. Cotreatment of cultures with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one prevented the SNAP-induced increase in GLUT4 protein. SNAP (10 microM) also induced significant phosphorylation of alpha-AMPK and acetyl-CoA carboxylase and translocation of phosphorylated alpha-AMPK to the nucleus. Furthermore, L6 myotubes exposed to 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) for 16 h presented an approximately ninefold increase in GLUT4 mRNA, whereas cotreatment with the non-isoform-specific NOS inhibitor N(G)-nitro-l-arginine methyl ester, prevented approximately 70% of this effect. In vivo, GLUT4 mRNA was increased 1.8-fold in the rat plantaris muscle 12 h after AICAR injection, and this induction was reduced by approximately 50% in animals cotreated with the neuronal and inducible nitric oxide synthases selective inhibitor 1-(2-trifluoromethyl-phenyl)-imidazole. We conclude that, in skeletal muscle, NO increases GLUT4 expression via a cGMP- and AMPK-dependent mechanism. The data are consistent with a role for NO in the regulation of AMPK, possibly via control of cellular activity of AMPK kinases and/or AMPK phosphatases.
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PMID:Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. 1766 90

The lipid peroxidation product 4-hydroxynonenal (4-HNE) is a signaling mediator with wide-ranging biological effects. In this paper, we report that disruption of mGsta4, a gene encoding the 4-HNE-conjugating enzyme mGSTA4-4, causes increased 4-HNE tissue levels and is accompanied by age-dependent development of obesity which precedes the onset of insulin resistance in 129/sv mice. In contrast, mGsta4 null animals in the C57BL/6 genetic background have normal 4-HNE levels and remain lean, indicating a role of 4-HNE in triggering or maintaining obesity. In mGsta4 null 129/sv mice, the expression of the acetyl-CoA carboxylase (ACC) transcript is enhanced several-fold with a concomitant increase in the tissue level of malonyl-CoA. Also, mitochondrial aconitase is partially inhibited, and tissue citrate levels are increased. Accumulation of citrate could lead to allosteric activation of ACC, further augmenting malonyl-CoA levels. Aconitase may be inhibited by 4-HNE or by peroxynitrite generated by macrophages which are enriched in white adipose tissue of middle-aged mGsta4 null 129/sv mice and, upon lipopolysaccharide stimulation, produce more reactive oxygen species and nitric oxide than macrophages from wild-type mice. Excessive malonyl-CoA synthesized by the more abundant and/or allosterically activated ACC in mGsta4 null mice leads to fat accumulation by the well-known mechanisms of promoting fatty acid synthesis and inhibiting fatty acid beta-oxidation. Our findings complement the recent report that obesity causes both a loss of mGSTA4-4 and an increase in the level of 4-HNE [Grimsrud, P. A., et al. (2007) Mol. Cell. Proteomics 6, 624-637]. The two reciprocal processes are likely to establish a positive feedback loop that would promote and perpetuate the obese state.
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PMID:Role of the electrophilic lipid peroxidation product 4-hydroxynonenal in the development and maintenance of obesity in mice. 1831 40


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