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

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

The biosynthesis of mevalonic acid, squalene, sterols, bile and fatty acids from [2-14C]malonyl-CoA and [1-14C]acetyl-CoA were studied. The activities of 3-hydroxy-3-methylglutaryl-CoA-reductase (GMG-CoA reductase) and acetyl-CoA carboxylase in subcellular fractions of human liver were determined. The livers of humans were used within 1.5-3 hours after clinical death. It was found that in all fractions studied (i.e. cell-free, 700 g, postmitochondrial, microsomal, cytosol) malonyl-CoA is incorporated into mevalonic acid more intensively than acetyl-CoA. The specific activity of GMG-CoA reductase in the microsomal and soluble fractions was essentially the same. Calculation of enzymatic activity per 1 g of wet mass of tissue showed that the bulk of activity is bound to the cytosol (soluble fraction) Malonyl-CoA can also act as a precursor of squalene, lanosterol, cholesterol and bile acids. The rate of malonyl-CoA incorporation into these compounds is practically the same as that of [2-14C] mevalonate but significantly exceeds that of acetyl-CoA at equal molar ratios of both substrates. Incorporation of malonyl-CoA into cholesterol occurs much more intensively in human liver than in rat liver, the cholesterol radioactivity reaching 18% of the total unsaponified fraction. Malonyl-CoA is a better substrate than acetyl-CoA both for fatty acid and for mevalonate, sterol and bile acid synthesis.
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PMID:[Biosynthesis of mevalonic acid, sterols and bile acids from acetyl-CoA and malonyl-CoA in the human liver]. 666 59

The effects of tunicamycin on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and cholesterol biosynthesis have been studied in cultured C-6 glial cells. Depending on culture conditions, exposure to tunicamycin caused either a marked inhibition of induction of HMG-CoA reductase activity or, under steady state conditions, a marked reduction in enzymatic activity. Incorporation of [14 C]acetate into sterols was affected similarly. After a 24-h exposure, a 50% reduction in reductase activity was observed with a concentration of 0.05 micrograms/ml, and a maximal, 65-70% reduction occurred with 0.10 micrograms/ml of the drug. The effect of tunicamycin on reductase activity and on sterol synthesis was apparent 4 h after addition of the drug and nearly maximal after 6 h. The relative specificity of the effect of tunicamycin was indicated by the finding of no change in the activities of NADPH-cytochrome c reductase, acetyl-CoA carboxylase, or fatty acid synthetase, in incorporation of [3H]leucine into total protein, or in the rate of increase in cellular protein and phospholipid at concentrations of tunicamycin that caused the marked effect on HMG-CoA reductase. The reversibility of the effect of tunicamycin was shown by observing total recovery of reductase activity within 24 h after removal of the drug following a 24-h exposure. That the effect of tunicamycin on reductase is related to the drug's effect on glycoprotein synthesis was shown in two ways. First, the range of concentrations over which tunicamycin led to the decrease in reductase activity was essentially identical with the range over which the drug led to a decrease in incorporation of [3H]mannose into protein. Second, incubation of C-6 cells with N-acetylglucosamine simultaneously with tunicamycin was accompanied by prevention of the drug's effect on both HMG-CoA reductase and glycoprotein synthesis. These data suggest that glycoprotein synthesis is necessary for the expression of HMG-CoA reductase activity and, thereby, cholesterol synthesis in glial cells. Moreover, a link between glycoprotein and cholesterol biosynthesis could play a role in the mediation of certain maturational events in cells of neural origin.
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PMID:Effect of tunicamycin on 3-hydroxy-3-methylglutaryl coenzyme A reductase in C-6 glial cells. 687 86

Swine were fed corn- or barley-based diets with, or without, culture filtrate (CF) of Trichoderma viride for 21 days. Weight gains were nonsignificantly but slightly increased by CF. The activities of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, acetyl-CoA carboxylase (ACX), fatty acid synthetase (FAS) and other lipogenic enzymes in several tissues were determined. Significant decreases in the activities of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in all tissues of swine fed the CF-diets were observed. The major site for the regulation of cholesterol biosynthesis was adipose tissue followed by the intestine, liver, lung and muscle in order of activity. The concentrations of cholesterol in serum and muscle were decreased 27% and 23%, respectively, by CF. ACX and FAS activities increased ca. 2-fold when CF was fed with either of the cereal-based diets. The major sites for fatty acid synthesis was the adipose tissue and, to a lesser extent, the liver. Very low rates of synthesis were detected in intestine, lung and muscle. Similar distributions of activities were found for related lipogenic enzymes.
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PMID:Effects of cereals and culture filtrate of Trichoderma viride on lipid metabolism of swine. 689 42

Various physical fractions of the barley kernel were fed to one-day-old female and male chickens to determine their effect on hepatic beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase and the lipogenic enzymes, acetyl-CoA carboxylase (ACX), malic enzyme (ME), citrate-cleavage enzyme (CCE) and fatty acid synthetase (FAS) at the subcellular level. Significant inhibition (p less than 0.01) of cholesterol biosynthesis accompanied by significant decreases in plasma cholesterol concentrations and induction of fatty acid synthesis were found in diets based on pearled barley, barley pearlings and a high-protein barley flour (HPBF: aleurone and subaleurone layers of barley endosperm) separated from the pearlings when compared to corn. Lower weight gains in 1- to 4-week-old birds fed the high-protein barley flour were found to be the result of lower feed consumption; pair feeding of 12-week-old birds with diets based on corn and high-protein barley flour produced equal weight gains in both treatments and significant reductions in hepatic HMG-CoA reductase, plasma cholesterol and induction in several lipogenic enzymes in birds fed the high-protein barley flour. Substitutions of 5-20% high-protein barley flour for corn in a corn-based diet produced significant weight gains (p less than 0.01) of 10 to 20% in 2-week-old chickens, inhibited cholesterol biosynthesis by 45-65% and produced a 3-fold increase in a fatty acid synthetase. The results indicate that HPBF contains an inhibitor(s) of cholesterol biosynthesis and a growth factor(s) when compared to a corn-based diet.
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PMID:Effects of different fractions of the barley kernel on the hepatic lipid metabolism of chickens. 716 70

AMP-activated protein kinase is a multisubstrate protein kinase that, in liver, inactivates both acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid synthesis, and 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. AICAR (5-amino 4-imidazolecarboxamide ribotide, ZMP) was found to stimulate up to 10-fold rat liver AMP-activated protein kinase, with a half-maximal effect at approximately 5 mM. In accordance with previous observations, addition to suspensions of isolated rat hepatocytes of 50-500 microM AICAriboside, the nucleoside corresponding to ZMP, resulted in the accumulation of millimolar concentrations of the latter. This was accompanied by a dose-dependent inactivation of both acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase. Addition of 50-500 microM AICAriboside to hepatocyte suspensions incubated in the presence of various substrates, including glucose and lactate/pyruvate, caused a parallel inhibition of both fatty acid and cholesterol synthesis. With lactate/pyruvate (10/1 mM), half-maximal inhibition was obtained at approximately 100 microM, and near-complete inhibition at 500 microM AICAriboside. These findings open new perspectives for the simultaneous control of triglyceride and cholesterol synthesis by pharmacological stimulators of AMP-activated protein kinase.
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PMID:Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. 773 63

To investigate the importance of factors influencing substrate availability for triacylglycerol biosynthesis on lipoprotein metabolism, the effects of two opposite-acting sulphur-substituted fatty acid analogues, tetradecylthioacetic acid and tetradecylthiopropionic acid were studied. Administration of tetradecylthioacetic acid to rats resulted in a reduction of plasma levels of triacylglycerols (44%) and cholesterol (26%). This was accompanied by a reduction in very-low-density lipoprotein (VLDL) triacylglycerols (48%), VLDL cholesterol (36%), low-density lipoprotein (LDL) cholesterol (36%) and high-density lipoprotein (HDL) triacylglycerols (50%), whereas HDL cholesterol levels did not change. Subsequently, the HDL/LDL-cholesterol ratio increased by 40%. The cholesterol-lowering effect was accompanied by a reduction in hydroxymethylglutaryl CoA (HMG-CoA) reductase activity (37%). Both mitochondrial and peroxisomal fatty acid oxidation increased (1.7-fold and 5.3-fold, respectively). Furthermore, there was a significant negative correlation between plasma triacylglycerols and mitochondrial fatty acid oxidation. Hepatic triacylglycerol synthesis was retarded, as indicated by a decrease in VLDL triacylglycerol secretion (40%), and by a reduced liver triacylglycerol content (29%). The activities of lipoprotein lipase and hepatic lipase in post-heparin plasma were not affected. Microsomal and cytosolic phosphatidate phosphohydrolase activities were inhibited (28% and 70%, respectively). Hepatic malonyl-CoA levels decreased by 29% and the total activity of acetyl-CoA carboxylase was reduced (23%). In hepatocytes treated with tetradecylthioacetic acid, mitochondrial fatty acid oxidation increased markedly (100%) and triacylglycerol secretion was reduced (40%). In tetradecylthiopropionic-acid-treated rats, a significant increase in both plasma and VLDL triacylglycerols was found (46% and 72%, respectively) but VLDL triacylglycerol secretion was unaffected. However, no effect on either plasma or lipoprotein cholesterol levels was seen. Mitochondrial fatty acid oxidation was decreased by 50% and hepatic triacylglycerol levels increased by 33%. In hepatocytes exposed to tetradecylthiopropionic acid, triacylglycerol synthesis increased (100%) while triacylglycerol secretion and fatty acid oxidation remained unaltered. The results illustrate that lipoprotein triacylglycerol levels can be modulated by changes in the availability of fatty acid substrate for triacylglycerol biosynthesis, mainly by affecting mitochondrial fatty acid oxidation. In addition, we demonstrate that suppression of rat hepatic HMG-CoA reductase activity during treatment with tetradecylthioacetic acid may contribute to a cholesterol-lowering effect.
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PMID:Hepatic fatty acid metabolism as a determinant of plasma and liver triacylglycerol levels. Studies on tetradecylthioacetic and tetradecylthiopropionic acids. 786 30

One independent and two overlapping rape cDNA clones have been isolated from a rape embryo library. We have shown that they encode a 2.3 kb and a 2.5 kb stretch of the full-length acetyl-CoA carboxylase (ACCase) cDNA, corresponding to the biotin-binding and transcarboxylase domains respectively. Using the cDNA in Northern-blot analysis we have shown that the mRNA for ACCase has a higher level of expression in rape seed than in rape leaf and has a full length of 7.5 kb. The level of expression during rape embryogenesis was compared with both oil deposition and expression of two fatty acid synthetase components enoyl-(acyl-carrier-protein) reductase and 3-oxoacyl-(acyl-carrier-protein) reductase. Levels of ACCase mRNA were shown to peak at 29 days after anthesis during embryonic development, similarly to enoyl-(acyl-carrier-protein) reductase and 3-oxoacyl-(acyl-carrier-protein) reductase mRNA. In addition, a full-length genomic clone (19 kb) of Arabidopsis ACCase has been isolated and partially sequenced. Analysis of the clone has allowed the first plant ACCase activity domains (biotin carboxylase-biotin binding-transcarboxylase) to be ordered and assigned. Southern-blot analysis using the Arabidopsis clone indicates that ACCase is a single-copy gene in Arabidopsis but is encoded by a small gene family in rape.
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PMID:Isolation of cDNAs from Brassica napus encoding the biotin-binding and transcarboxylase domains of acetyl-CoA carboxylase: assignment of the domain structure in a full-length Arabidopsis thaliana genomic clone. 791 5

AMP-activated protein kinase (AMPK) phosphorylates and inactivates acetyl-CoA carboxylase and beta-hydroxy beta-methylglutaryl-coenzyme A (HMG-CoA) reductase which are the major enzymes involved in fatty acid and lipid biosyntheses. The AMPK gene from rat (rAMPK) has recently been cloned [Carling et al., J. Biol. Chem. 269 (1994) 11442-11448]. In order to study the structure and function of the human AMPK gene (hAMPK), we have cloned the gene, and report in this communication its nucleotide (nt) sequence, tissue distribution and chromosomal location. Our results show that the ORF of hAMPK encodes 552 amino acids (aa) (62.250 kDa) and is highly conserved with rAMPK with identities of 97.3 and 90% at the aa and nt levels, respectively. The hAMPK gene bears homology to a yeast protein kinase-encoding gene (snf1) that regulates carbohydrate metabolism, and also with three other genes encoding SNF1-like kinases from different plant species, namely Arabidopsis thaliana, Hordeum vulgare and Secale cereale. As determined by fluorescent in situ hybridization of a human metaphase chromosome spread, hAMPK maps to chromosome 1p31. The size of the hAMPK transcript is 8.5 kb and the transcription start point (tsp) is located approx. 46 bp upstream from the ATG codon. While 10-15% of AMPK is alternatively spliced in most tissues of the rat, our RT-PCR analyses of the hAMPK mRNA did not reveal the presence of any alternatively spliced form of the gene in human tissues. An interesting aspect of AMPK is that its expression, unlike in rat liver, could not be detected in human liver, and thus the purported role of the gene in controlling fatty-acid synthesis in the human liver remains to be determined.
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PMID:Characterization and chromosomal localization of the human homologue of a rat AMP-activated protein kinase-encoding gene: a major regulator of lipid metabolism in mammals. 795 15

Administration of tetradecylthioacetic acid (a 3-thia fatty acid) increases mitochondrial and peroxisomal beta-oxidative capacity and carnitine palmitoyltransferase activity, but reduces free fatty acid and triacylglycerol levels in plasma compared to palmitic acid-treated rats and controls. The decrease in plasma triacylglycerol was accompanied by a reduction (56%) in VLDL-triacylglycerol. Prolonged supplementation of tetradecylthioacetic acid caused a significant increase in lipogenic enzyme activities (ATP-citrate lyase and acetyl-CoA carboxylase) and diacylglycerol acyltansferase, but did not affect phosphatidate phosphohydrolase. Plasma cholesterol, LDL- and HDL-cholesterol levels were reduced. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity was, however, stimulated in 3-thia fatty acid-treated rats compared to controls. In addition. the mRNAs of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and LDL-receptor were increased. Tetradecylthioacetic acid administration affected the fatty acid composition in plasma and liver by increasing the amount of monoenes, especially 18:1(n-9), mostly at the expense of omega-3 fatty acids. Compared to liver a large amount of tetradecylthioacetic acid accumulated in the heart, and this accumulation was accompanied by an increase in omega-3 fatty acids, particularly 22:6(n-3) and a decrease in omega-6 fatty acids, mainly 20:4(n-6). The results show that the hypolipidemic effect of tetradecylthioacetic acid is sustained after prolonged administration and may, at least in part, be due to increased fatty acid oxidation and upregulated LDL-receptor gene expression. The increase in lipogenic enzyme activities as well as increased 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, may be compensatory mechanisms to maintain cellular integrity. Decreased level of 20:4(n-6) combined with increased omega-3/omega-6 ratio in cardiac tissue after tetradecylthioacetic acid treatment may have influence on membrane dynamics and function.
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PMID:Long-term effect of tetradecylthioacetic acid: a study on plasma lipid profile and fatty acid composition and oxidation in different rat organs. 865 42

We examined the effect of pravastatin sodium (pravastatin), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on fatty acid synthesis in rat liver. The repeated administration of pravastatin to rats at 250 mg/kg for 7 days led to a 2.8-fold increase in fatty acid synthesis in the liver. The diurnal change of fatty acid synthesis was not affected by the treatment. Hepatic fatty acid synthase activity was increased 3.2-fold, while acetyl-CoA carboxylase activity was not changed by the repeated administration of pravastatin. In rat hepatocytes, the incubation with 2 microg/ml pravastatin for 24 h increased fatty acid synthase activity 1.5-fold, as well as HMG-CoA reductase activity 2.8-fold. These results suggest that HMG-CoA reductase inhibitors might increase fatty acid synthesis in vivo through the induction of hepatic fatty acid synthase.
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PMID:Induction of fatty acid synthesis by pravastatin sodium in rat liver and primary hepatocytes. 921 6


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