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)

Fenofibrate is a potent hypolipidemic agent that lowers plasma lipid levels and may thus decrease the incidence of atherosclerosis. Here we investigated the molecular mechanism of fenofibrate's hypolipidemic action by characterizing its in vivo effects on the expression of mRNAs and the activities of pivotal enzymes in cholesterol and triglyceride metabolism in the hamster. Treatment of hamsters with fenofibrate led to a dose-dependent reduction in serum cholesterol concentrations. Studies on the incorporation of [(14)C]acetate and [(14)C]mevalonate into cholesterol suggested that this effect occurs primarily through inhibition of cholesterol biosynthesis at steps prior to mevalonate. Fenofibrate decreased levels of hepatic enzyme activities and mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase. A potential mechanism for transcriptional regulation of these enzymes is via SREBP-2 that we found to be suppressed 2-fold by fenofibrate. Fenofibrate also lowered circulatory triglyceride levels. In keeping with the effect, we observed strong suppression of fatty acid synthase, acetyl-CoA carboxylase and apolipoprotein C-III mRNA and stimulation of lipoprotein lipase and acyl-CoA oxidase mRNA in the liver of fenofibrate-treated hamsters. These observations suggest that the effect of fenofibrate on triglyceride metabolism is likely to be a result of both decreased fatty acid synthesis and increased lipoprotein lipase and acyl-CoA oxidase gene expression in the liver. Surprisingly, alterations in lipoprotein lipase, acyl-CoA oxidase, acetyl-CoA carboxylase, and apolipoprotein C-III could not be observed in hamster hepatocytes incubated with fenofibric acid in vitro. These observations raise the possibility that changes in these genes may be secondary to the metabolic alterations occurring in animals but not in cultured cells and thus that the effect of fenofibrate on these genes may be indirect.
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PMID:Regulation of lipid metabolism and gene expression by fenofibrate in hamsters. 1173 32

The de novo synthesis of fatty acids in plants occurs in the plastids through the activity of fatty acid synthetase. The synthesis of the malonyl-coenzyme A that is required for acyl-chain elongation requires the import of metabolites from the cytosol and their subsequent metabolism. Early studies had implicated acetate as the carbon source for plastidial fatty acid synthesis but more recent experiments have provided data that argue against this. A range of cytosolic metabolites including glucose 6-phosphate, malate, phosphoenolpyruvate and pyruvate support high rates of fatty acid synthesis by isolated plastids, the relative utilisation of which depends upon the plant species and the organ from which the plastids are isolated. The import of these metabolites occurs via specific transporters on the plastid envelope and recent advances in the understanding of the role of these transporters are discussed. Chloroplasts are able to generate the reducing power and ATP required for fatty acid synthesis by capture of light energy in the reactions of photosynthetic electron transport. Regulation of chloroplast fatty acid synthesis is mediated by the response of acetyl-CoA carboxylase to the redox state of the plastid, which ensures that the carbon metabolism is linked to the energy status. The regulation of fatty acid synthesis in plastids of heterotrophic cells is much less well understood and is of particular interest in the tissues that accumulate large amounts of the storage oil, triacylglycerol. In these heterotrophic cells the plastids import ATP and oxidise imported carbon sources to produce the required reducing power. The sequencing of the genome of Arabidopsis thaliana has now enabled a number of aspects of plant fatty acid synthesis to be re-addressed, particularly those areas in which in vitro biochemical analysis had provided equivocal answers. Examples of such aspects and future opportunities for our understanding of plant fatty acid synthesis are presented and discussed.
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PMID:Carbon flux and fatty acid synthesis in plants. 1175 83

Endurance training has been shown to increase fat oxidation both at rest and during exercise. However, most exercise training studies have been performed at high exercise intensity in well-trained athletes, and not much is known about the effect of a low-intensity training program on fat oxidation capacity in lean sedentary humans. Here, we examine the effect of 3-month low-intensity training program on total and intramuscular triglyceride (IMTG)- and/or VLDL-derived fat oxidation capacity and skeletal muscle mRNA expression. Six healthy untrained subjects (aged 43 +/- 2 years, BMI 22.7 +/- 1.1 kg/ m(2), V(O)(2max) 3.2 +/- 0.2 l/min) participated in a supervised 12-week training program at 40% V(O)(2max) three times weekly. Total and plasma-derived fatty acid oxidation at rest and during 1 h exercise was measured using [(13)C]palmitate, and in a separate test, [(13)C]acetate recovery was determined. Muscle biopsies were taken after an overnight fast. Total fat oxidation during exercise increased from 1,241 +/- 93 to 1,591 +/- 130 micromol/min (P = 0.06), and IMTG- and/or VLDL-derived fatty acid oxidation increased from 236 +/- 84 to 639 +/- 172 micromol/min (P = 0.09). Acetyl-CoA carboxylase-2 mRNA expression was significantly decreased after training (P = 0.005), whereas lipoprotein lipase mRNA expression tended to increase (P = 0.07). In conclusion, a minimal amount of physical activity tends to increase fat oxidation and leads to marked changes in the expression of genes encoding for key enzymes in fat metabolism.
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PMID:The effect of a 3-month low-intensity endurance training program on fat oxidation and acetyl-CoA carboxylase-2 expression. 1208 53

The hindlimb-suspended rat was used as animal model to investigate the effects induced by immobilization of the skeletal muscle in the expression of the genes encoding hepatic lipogenic enzymes. Following a 14-day period of immobilization, rats were injected intraperitoneally with radioactive acetate, and the labeling of hepatic lipids and cholesterol was evaluated 15 min after the isotope injection. The incorporation of labeled acetate in lipids and cholesterol was almost three times higher in the liver of immobilized rats than in control animals as a consequence of the enhanced transcription of the genes encoding acetyl-CoA synthase, acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase. The high expression of the key enzymes for fatty acid and cholesterol synthesis induced by immobilization was not paralleled by an increase of the hepatic sterol-regulatory element binding protein (SREBP)-1 and SREBP-2 mRNA content. However, the expression of the mature form of SREBP-1 and SREBP-2 was higher in the nuclear fraction of immobilized rat liver than in controls due to a significant increase of the cleavage of the native proteins. Immobilization also affected the expression of proteins involved in lipid degradation. In fact, the hepatic content of peroxisome proliferator-activated receptor-alpha (PPARalpha) mRNA and of PPARalpha target genes encoding carnitine palmitoyl transferase-1 and acyl-CoA oxidase were significantly increased upon immobilization.
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PMID:Enhanced expression of hepatic lipogenic enzymes in an animal model of sedentariness. 1256 63

To elucidate the essential functions of acetyl-CoA carboxylase (ACC1FAS3) in Saccharomyces cerevisiae, a temperature-sensitive mutant (acc1(ts)) was constructed. When the acc1(ts) cells were synchronized in G(1) phase with alpha-factor at the permissive temperature of 24 degrees C and then released from the blockade and incubated at the restrictive temperature of 37 degrees C, 95% of the cell population became arrested at the G(2)M phase of the cell cycle despite the presence of fatty acids (C(14)-C(26)) in the medium. These cells developed large undivided nuclei, and the spindles of the arrested mutant cells were short. Shifting the G(2) arrested cells back to the permissive temperature resulted in a reversal of the cell-cycle arrest, with cells initiating mitosis. However, after 3 h of incubation at 37 degrees C, G(2) arrested mutant cells lost viability and displayed a uniquely altered nuclear envelope. Using [1-(14)C]acetate as a precursor for fatty acids synthesis, we identified the phospholipids and sphingolipids derived from acc1(ts) cells and wild-type cells at 24 degrees C and 37 degrees C, respectively. The levels of inositol-ceramides [IPC, MIPC, and M(IP)(2)C] and very long-chain fatty acids C(24) and C(26) declined sharply in the G(2)M arrested cells because of ACC inactivation. Shifting the acc1(ts) cells to 24 degrees C after 2 h of incubation at 37 degrees C resulted in reactivation of the ACC and elevation of the ceramides and very long-chain fatty acid syntheses with normal cell-cycle progression. In contrast, synthesis of wild-type inositol-ceramides, C(24) and C(26), fatty acids were elevated on incubation at 37 degrees C and declined when the cells shifted to the permissive temperature of 24 degrees C.
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PMID:A Saccharomyces cerevisiae mutant strain defective in acetyl-CoA carboxylase arrests at the G2/M phase of the cell cycle. 1262 51

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.
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PMID:Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. 1461 31

This paper describes the antitumoral activity of branched-chain fatty acid (BCFA) in human breast cancer cells with an emphasis on its effect on fatty acid biosynthesis. First, the relationship between chain-length and antitumoral activity was studied. The highest activity was observed with iso-16:0, and the activity decreased with increase or decrease of the chain-lengths from C16:0. Anteiso-BCFA, as well as iso-series, was cytotoxic to the breast cancer cells. Cytotoxicity of BCFA was comparable to that of conjugated linoleic acid known as antitumoral fatty acid. Incubation of breast cancer cells with BCFA (13-methyltetradecanoic acid) significantly reduced the [14C] acetate incorporation into free fatty acid and fatty acid esters, showing the inhibition of fatty acid biosynthesis by BCFA. Examination of substrate level effect found that BCFA slightly inhibited fatty acid synthetase and acetyl-CoA carboxylase, and significantly the glucose-6-phosphate dehydrogenase which was the main NADPH generating system in breast cancer cells. The present study thus suggests that BCFA synthetically lowers the fatty acid biosynthesis by reducing the precursors, in addition to its direct inhibitory effect on fatty acid synthetase.
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PMID:Effect of branched-chain fatty acids on fatty acid biosynthesis of human breast cancer cells. 1524 18

Mammary epithelial cells, which express and secrete leptin into milk, accumulate triacylglycerol (TAG). We examined effects on the accumulation of cytosolic TAG of addition of short- (acetate and butyrate) or medium- (octanoate) chain fatty acids to the medium bathing bovine mammary epithelial cells (bMEC). Octanoate stimulated the accumulation of TAG in a concentration-dependent manner from 1 to 10 mM and increased lipid droplet formation and mRNA expression of CD36 (a fatty acid translocase). Additionally, expression of a peroxisome proliferator activated receptor (PPAR) gamma 2 protein that is a lipid-activated transcription factor, was increased by the addition of acetate or octanoate. However, leptin mRNA expression was significantly reduced by addition of acetate or butyrate. Both short- and medium-chain fatty acids inhibited acetyl coenzyme A carboxylase (ACC) activities, which is pivotal in lipid synthesis, but elevated expression of uncoupling protein 2 (UCP2) mRNA, which is important in energy expenditure. These results suggest that octanoate induces cytosolic TAG accumulation and the formation of lipid droplets, and that acetate and butyrate inhibit leptin expression and lipid synthesis in bMEC.
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PMID:Octanoate stimulates cytosolic triacylglycerol accumulation and CD36 mRNA expression but inhibits acetyl coenzyme A carboxylase activity in primary cultured bovine mammary epithelial cells. 1560 5

Three-year-old Angus x Gelbvieh beef cows nutritionally managed to achieve a BCS of 4 +/- 0.07 (479.3 +/- 36.3 kg of initial BW) or 6 +/- 0.07 (579.6 +/- 53.1 kg of initial BW) at parturition were used in a 2-yr experiment (n = 36/yr) to determine the effects of BCS at parturition and postpartum lipid supplementation on cow adipose tissue lipogenesis. Beginning 3 d postpartum, cows within each BCS were randomly assigned to be fed hay and a low-fat control supplement or supplements with either cracked high-linoleate safflower seeds or cracked high-oleate safflower seeds until d 60 of lactation. Diets were formulated to be isonitrogenous and isocaloric, and safflower seed diets provided 5% DMI as fat. Adipose tissue biopsies were collected near the tail-head region of cows on d 30 and 60 of lactation. Dietary treatment did not affect (P > or = 0.43) adipose tissue lipogenesis. Body condition score at parturition did not affect acetate incorporation into lipid (P = 0.53) or activity of acetyl CoA carboxylase (P = 0.77) or fatty acid synthase (P = 0.18). Lipoprotein lipase activity and palmitate incorporation into triacyl-glycerol tended to be greater (P = 0.06), and palmitate esterification into total acylglycerols was greater (P = 0.01) in cows with a BCS of 4 at parturition. Mean activity of acetyl-CoA carboxylase (P < 0.001), lipoprotein lipase (P = 0.01), and rate of palmitate incorporation into monoacylglycerol (P = 0.02), diacylglycerol (P = 0.001), triacylglycerol (P = 0.003), and total acylglycerols (P = 0.002) were greater at d 30 than d 60, suggesting a greater proclivity for fatty acid biosynthesis and esterification by adipose tissue at d 30 of lactation. Although dietary lipid supplementation did not affect adipose tissue lipogenesis, results suggest that cows with a BCS of 4 at parturition have a greater propensity to deliver exogenously derived fatty acids to the adipocyte surface and incorporate preformed fatty acids into acylglycerols as stored adipocyte lipid. Additionally, cows in early lactation seemed to be able to synthesize and incorporate more fatty acids into stored lipid than cows during peak lactation.
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PMID:Effects of body condition score at parturition and postpartum supplemental fat on adipose tissue lipogenic activity of lactating beef cows. 1642 68

Chloroplasts isolated from immature leaves of spinach (Spinacia oleracea) differ in enzyme levels from those isolated from mature leaves. On a chlorophyll basis, immature chloroplast preparations had 5- to 6-fold higher capacity to synthesize fatty acids from 2-(14)C-acetate compared to plastids isolated from mature leaves. This difference was correlated with higher activities for the enzymes, acetyl coenzyme A synthetase, malonyl coenzyme A synthetase, acetyl coenzyme A carboxylase, and oleyl coenzyme A transferase in plastid pressates obtained from immature leaves. Disrupted chloroplast preparations from both mature and immature leaves retained the ability to incorporate 2-(14)C-acetate into fatty acids in a pattern similar to that by isolated chloroplasts. 2-(14)C-Acetate, 2-(14)C-acetyl coenzyme A, 2-(14)C-malonate, and 1,3-(14)C malonyl coenzyme A were readily incorporated into a number of fatty acids. Moreover, the synthesis of oleate by chloroplast pressates from these substrates was strongly inhibited by KCN, flavin adenine mononucleotides and dinucleotides, and anaerobic conditions, while linolenic acid synthesis was unaffected by these compounds.
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PMID:Fat Metabolism in Higher Plants: LVII. A Comparison of Fatty Acid-Synthesizing Enzymes in Chloroplasts Isolated from Mature and Immature Leaves of Spinach. 1665 18


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