Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-isoform of acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
...
PMID:Malonyl-CoA, fuel sensing, and insulin resistance. 988 45

Exercise induces a decline in liver malonyl-CoA, an inhibitor of carnitine palmitoyltransferase-1. The purpose of these experiments was to determine whether this decrease in malonyl-CoA is accompanied by an activation of AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase (ACC). Rats were killed at rest, after 10 min of running at 32 m/min up a 15% grade or at 0, 15, or 60 min postexercise after 120 min of running at 16 m/min. There was no significant difference in AMPK and ACC activities after 120 min of exercise, although a trend toward a decrease in ACC and an increase in AMPK was noted 15 min postexercise. After 10 min at 32 m/min, however, maximal ACC activity decreased from 487 +/- 27 to 280 +/- 39 nmol. g-1. min-1, and the activation constant for citrate activation of ACC increased from 5.9 to 12.5 mM. AMPK activity increased from a resting value of 4.7 +/- 0.4 to 9.8 +/- 2.0 pmol. mg-1. min-1 after exercise. These data provide indirect evidence of phosphorylation and inactivation of liver ACC during heavy exercise. In contrast, the decrease in malonyl-CoA during long-term, low-intensity exercise may occur by mechanisms other than phosphorylation of ACC.
...
PMID:Liver AMP-activated protein kinase and acetyl-CoA carboxylase during and after exercise. 993 Dec 6

The aim of the present study was to investigate the hepatic regulation and beta-oxidation of long-chain fatty acids in peroxisomes and mitochondria, after 3-thia- tetradecylthioacetic acid (C14-S-acetic acid) treatment. When palmitoyl-CoA and palmitoyl-L-carnitine were used as substrates, hepatic formation of acid-soluble products was significantly increased in C14-S-acetic acid treated rats. Administration of C14-S-acetic acid resulted in increased enzyme activity and mRNA levels of hepatic mitochondrial carnitine palmitoyltransferase (CPT)-II. CPT-II activity correlated with both palmitoyl-CoA and palmitoyl-L-carnitine oxidation in rats treated with different chain-length 3-thia fatty acids. CPT-I activity and mRNA levels were, however, marginally affected. The hepatic CPT-II activity was mainly localized in the mitochondrial fraction, whereas the CPT-I activity was enriched in the mitochondrial, peroxisomal, and microsomal fractions. In C14-S-acetic acid-treated rats, the specific activity of peroxisomal and microsomal CPT-I increased, whereas the mitochondrial activity tended to decrease. C14-S-Acetyl-CoA inhibited CPT-I activity in vitro. The sensitivity of CPT-I to malonyl-CoA was unchanged, and the hepatic malonyl-CoA concentration increased after C14-S-acetic acid treatment. The mRNA levels of acetyl-CoA carboxylase increased. In hepatocytes cultured from palmitic acid- and C14-S-acetic acid-treated rats, the CPT-I inhibitor etomoxir inhibited the formation of acid-soluble products 91 and 21%, respectively. In contrast to 3-thia fatty acid treatment, eicosapentaenoic acid treatment and starvation increased the mitochondrial CPT-I activity and reduced its malonyl-CoA sensitivity. Palmitoyl-L-carnitine oxidation and CPT-II activity were, however, unchanged after either EPA treatment or starvation. The results from this study open the possibility that the rate control of mitochondrial beta-oxidation under mitochondrion and peroxisome proliferation is distributed between an enzyme or enzymes of the pathway beyond the CPT-I site after 3-thia fatty acid treatment. It is suggested that fatty acids are partly oxidized in the peroxisomes before entering the mitochondria as acylcarnitines for further oxidation.
...
PMID:3-Thia fatty acid treatment, in contrast to eicosapentaenoic acid and starvation, induces gene expression of carnitine palmitoyltransferase-II in rat liver. 1038 Jan 16

Malonyl-CoA acutely regulates fatty acid oxidation in liver in vivo by inhibiting carnitine palmitoyltransferase. Thus rapid increases in the concentration of malonyl-CoA, accompanied by decreases in long-chain fatty acyl carnitine (LCFA-carnitine) and fatty acid oxidation have been observed in liver of fasted-refed rats. It is less clear that it plays a similar role in skeletal muscle. To examine this question, whole body respiratory quotients (RQ) and the concentrations of malonyl-CoA and LCFA-carnitine in muscle were determined in 48-h-starved rats before and at various times after refeeding. RQ values were 0.82 at baseline and increased to 0.93, 1. 0, 1.05, and 1.09 after 1, 3, 12, and 18 h of refeeding, respectively, suggesting inhibition of fat oxidation in all tissues. The increases in RQ at each time point correlated closely (r = 0.98) with increases (50-250%) in the concentration of malonyl-CoA in soleus and gastrocnemius muscles and decreases in plasma FFA and muscle LCFA-carnitine levels. Similar changes in malonyl-CoA and LCFA-carnitine were observed in liver. The increases in malonyl-CoA in muscle during refeeding were not associated with increases in the assayable activity of acetyl-CoA carboxylase (ACC) or decreases in the activity of malonyl-CoA decarboxylase (MCD). The results suggest that, during refeeding after a fast, decreases in fatty acid oxidation occur rapidly in muscle and are attributable both to decreases in plasma FFA and increases in the concentration of malonyl-CoA. They also suggest that the increase in malonyl-CoA in this situation is not due to changes in the assayable activity of either ACC or MCD or an increase in the cytosolic concentration of citrate.
...
PMID:Malonyl-CoA content and fatty acid oxidation in rat muscle and liver in vivo. 1091 24

Multiple adult morbidities are associated with intrauterine growth retardation (IUGR) including dyslipidemia. We hypothesized that uteroplacental insufficiency and subsequent IUGR in the rat would lead to altered hepatic fatty acid metabolism. To test this hypothesis, we quantified hepatic mRNA levels of acetyl-CoA carboxylase (ACC), carnitine palmitoyltransferase (CPTI), the beta-oxidation-trifunctional protein (HADH), fasting serum triglycerides, and hepatic malonyl-CoA levels at different ages in control and IUGR rats. Fetal gene expression of all three enzymes was decreased. Juvenile gene expression of CPTI and HADH continued to be decreased, whereas gene expression of ACC was increased. Serum triglycerides were unchanged. A sex-specific response was noted in the adult rats. In males, serum triglycerides, hepatic malonyl-CoA levels, and ACC mRNA levels were significantly increased, and CPTI and HADH mRNA levels were significantly decreased. In contrast, the female rats demonstrated no significant changes in these variables. These results suggest that uteroplacental insufficiency leads to altered hepatic fatty acid metabolism that may contribute to the adult dyslipidemia associated with low birth weight.
...
PMID:Uteroplacental insufficiency alters hepatic fatty acid-metabolizing enzymes in juvenile and adult rats. 1112 50

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.
...
PMID:Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. 1134 29

The metabolic effects of feeding soyabean oil instead of an isoenergetic amount of maize starch plus glucose were studied in ponies. Twelve adult Shetland ponies were given a control diet (15 g fat/kg DM) or a high-fat diet (118 g fat/kg DM) according to a parallel design. The diets were fed for 45 d. Plasma triacylglycerol (TAG) concentrations decreased by 55 % following fat supplementation. Fat feeding also reduced glycogen concentrations significantly by up to 65 % in masseter, gluteus and semitendinosus muscles (P < 0.05 and P < 0.01 and P < 0.01 respectively). The high-fat diet significantly increased the TAG content of semitendinosus muscle by 80 % (P < 0.05). Hepatic acetyl-CoA carboxylase and fatty acid synthase activities were 53 % (P < 0.01) and 56 % (P < 0.01) lower respectively in the high-fat group, but diacylglycerol acyltransferase activity was unaffected. Although carnitine palmitoyltransferase-I (CPT-I) activity in liver mitochondria was not influenced, fat supplementation did render CPT-I less sensitive to inhibition by malonyl-CoA. There was no significant effect of diet on the activity of phosphofructokinase in the different muscles. The activity of citrate synthase was raised significantly (by 25 %; P < 0.05) in the masseter muscle of fat-fed ponies, as was CPT-I activity (by 46 %; P < 0.01). We conclude that fat feeding enhances both the transport of fatty acids through the mitochondrial inner membrane and the oxidative capacity of highly-aerobic muscles. The higher oxidative ability together with the depressed rate of de novo fatty acid synthesis in liver may contribute to the dietary fat-induced decrease in plasma TAG concentrations in equines.
...
PMID:High fat intake lowers hepatic fatty acid synthesis and raises fatty acid oxidation in aerobic muscle in Shetland ponies. 1143 62

Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy.
...
PMID:Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. 1144 28

We observed earlier that increased skeletal muscle lipid content in the hereditary hypertriglyceridemic (hHTg) rat is accompanied by a decline in plasma leptin. Leptin has recently been shown to enhance peripheral insulin sensitivity by decreasing the tissue triglyceride accumulation, possibly through regulation of fatty acid oxidation and lipogenesis. Thus, to test the hypothesis that insulin resistance and increased skeletal muscle lipid accumulation in hHTg rats are due to a defect in lipid catabolism, we measured mitochondrial and peroxisomal fatty acid oxidation and malonyl-CoA and acetyl-CoA carboxylase-2 content in skeletal muscles of these animals. In addition, we investigated possible molecular mechanisms responsible for the lower leptin levels in hHTg rats by measuring leptin and leptin-receptor (Ob-Ra) mRNA levels. We found the following: (1) in spite of a higher skeletal muscle malonyl-CoA content and an increased sensitivity of carnitine palmitoyltransferase-1 to malonyl-CoA, carnitine palmitoyltransferase-1 activity in muscle of hHTg rats was normal; (2) increased peroxisomal fatty acid oxidation did not seem to be sufficient to prevent the tissue lipid accumulation in these animals; (3) both lower leptin production by white adipose tissue and increased leptin uptake seem to be responsible for lower circulating leptin levels and therefore lower fatty acid catabolism.
...
PMID:An increase in peroxisomal fatty acid oxidation is not sufficient to prevent tissue lipid accumulation in hHTg rats. 1207 37

C75, an inhibitor of fatty acid synthase (FAS), induces apoptosis in cultured human cancer cells. Its proposed mechanism of action linked high levels of malonyl-CoA after FAS inhibition to potential downstream effects including inhibition of carnitine palmitoyltransferase-1 (CPT-1) with resultant inhibition of fatty acid oxidation. Recent data has shown that C75 directly stimulates CPT-1 increasing fatty acid oxidation in MCF-7 human breast cancer cells despite inhibitory concentrations of malonyl-CoA. In light of these findings, we have studied fatty acid metabolism in MCF7 human breast cancer cells to elucidate the mechanism of action of C75. We now report that: (a) in the setting of increased fatty acid oxidation, C75 inhibits fatty acid synthesis; (b) C273, a reduced form of C75, is unable to inhibit fatty acid synthesis and is nontoxic to MCF7 cells; (c) C75 and 5-(tetradecyloxy)-2-furoic acid (TOFA), an inhibitor of acetyl-CoA carboxylase, both cause a significant reduction of fatty acid incorporation into phosphatidylcholine, the major membrane phospholipid, within 2 h; (d) pulse chase studies with [(14)C]acetate labeling of membrane lipids show that both C75 and TOFA accelerate the decay of (14)C-labeled lipid from membranes within 2 h; (e) C75 also promotes a 2-3-fold increase in oxidation of membrane lipids within 2 h; and (f) because interference with phospholipid synthesis during S phase is known to trigger apoptosis in cycling cells, we performed double-labeled terminal deoxynucleotidyltransferase-mediated nick end labeling and BrdUrd analysis with both TOFA and C75. C75 triggered apoptosis during S phase, whereas TOFA did not. Moreover, application of TOFA 2 h before C75 blocked the C75 induced apoptosis, whereas etomoxir did not. Taken together these data indicate that FAS inhibition and its downstream inhibition of phospholipid production is a necessary part of the mechanism of action of C75. CPT-1 stimulation does not likely play a role in the cytotoxic response. The continued ability of TOFA to rescue cancer cells from C75 cytotoxicity implies a proapoptotic role for malonyl-CoA independent of CPT-1 that selectively targets cancer cells as they progress into S phase.
...
PMID:Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. 1461 31


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

---