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 TSC13/YDL015c gene was identified in a screen for suppressors of the calcium sensitivity of csg2Delta mutants that are defective in sphingolipid synthesis. The fatty acid moiety of sphingolipids in Saccharomyces cerevisiae is a very long chain fatty acid (VLCFA) that is synthesized by a microsomal enzyme system that lengthens the palmitate produced by cytosolic fatty acid synthase by two carbon units in each cycle of elongation. The TSC13 gene encodes a protein required for elongation, possibly the enoyl reductase that catalyzes the last step in each cycle of elongation. The tsc13 mutant accumulates high levels of long-chain bases as well as ceramides that harbor fatty acids with chain lengths shorter than 26 carbons. These phenotypes are exacerbated by the deletion of either the ELO2 or ELO3 gene, both of which have previously been shown to be required for VLCFA synthesis. Compromising the synthesis of malonyl coenzyme A (malonyl-CoA) by inactivating acetyl-CoA carboxylase in a tsc13 mutant is lethal, further supporting a role of Tsc13p in VLCFA synthesis. Tsc13p coimmunoprecipitates with Elo2p and Elo3p, suggesting that the elongating proteins are organized in a complex. Tsc13p localizes to the endoplasmic reticulum and is highly enriched in a novel structure marking nuclear-vacuolar junctions.
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PMID:Tsc13p is required for fatty acid elongation and localizes to a novel structure at the nuclear-vacuolar interface in Saccharomyces cerevisiae. 1111 86

Several nondigestible but fermentable dietary carbohydrates are able to regulate lipemia and triglyceridemia in both humans and animals. The mechanism of their serum lipid-lowering effect remains to be elucidated. Oligofructose, which is a mixture of nondigestible and fermentable fructans, can decrease triacylglycerol in VLDL when given to rats. The triacylglycerol-lowering action of oligofructose is due to a reduction of de novo fatty acid synthesis in the liver through inhibition of all lipogenic enzymes, namely acetyl-CoA carboxylase (EC 6.4.1.2), fatty acid synthase, malic enzyme (EC 1.1.1.40), ATP citrate lyase (EC 4.1.3.8), and glucose-6-phosphate dehydrogenase (EC 1.1.1.49). Our results suggest that oligofructose decreases lipogenic enzyme gene expression. Postprandial insulin and glucose concentrations are low in the serum of oligofructose-fed animals and this could explain, at least partially, the metabolic effect of oligofructose. Moreover, some events occurring in the gastrointestinal tract after oligofructose feeding could be involved in the antilipogenic effect of this fructan: the production of propionate through fermentation, a modulation of the intestinal production of incretins (namely glucose-dependent insulinotropic peptide and glucagon-like peptide-1), or the modification of the availability of digestible carbohydrates. Recent studies showed that the hypotriglyceridemic effect of fructans also occurs in humans.
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PMID:Effects of fructans-type prebiotics on lipid metabolism. 1115 57

Peroxisome proliferator-activated receptor alpha (PPAR alpha)-null mice were used to investigate the nature of the relationship between the normal circadian rhythm of hepatic PPAR alpha expression and the expression of the lipogenic and cholesterogenic sterol regulatory element-binding protein (SREBP)-regulated genes, acetyl-CoA carboxylase, fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR). The expression of FAS and HMG-CoAR varied rhythmically over the diurnal cycle in the normal mice, with patterns that were the opposite of that of PPAR alpha. The diurnal variation of lipogenic and cholesterogenic gene expression was attenuated or abolished in the PPAR alpha-null mice. This resulted in decreased expression compared with normal mice, but only during the dark phase of the cycle, when food intake was high. The diurnal variation in hepatic fatty acid and cholesterol synthesis was also abolished in the PPAR alpha-null animals and the variations in the concentration of plasma triacylglycerol, nonesterified fatty acids, and cholesterol were all attenuated. The failure of HMG-CoAR expression to increase during the feeding period in the PPAR alpha-null mice was associated with a decrease in hepatic nonesterified cholesterol content and an increase in cholesteryl ester compared with normal mice. There was no defect in the downregulation of hepatic HMG-CoAR mRNA in response to dietary cholesterol in the PPAR alpha-null mice. Under these conditions, hepatic PPAR gamma expression increased in both the control and PPAR alpha-deficient mice. The results suggest that PPAR alpha-deficiency disturbs the normal circadian regulation of certain SREBP-sensitive genes in the liver, but does not affect their response to dietary cholesterol. -- Patel, D. D., B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons. Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice. J. Lipid Res. 2001. 42: 328--337.
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PMID:Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice. 1125 43

The rat acetyl-CoA carboxylase (ACC) alpha gene is transcribed from two promoters, denoted PI and PII, that direct regulated expression in a tissue-specific manner. Induction of ACC, the rate-controlling enzyme of fatty acid biosynthesis, occurs in the liver in response to feeding of a high carbohydrate, low fat diet, conditions that favor enhanced lipogenesis. This induction is mainly due to increases in PI promoter activity. We have used primary cultured hepatocytes from the rat to investigate glucose regulation of ACC expression. Glucose and insulin synergistically activated expression of ACC mRNAs transcribed from the PI promoter with little or no effect on PII mRNAs. Glucose treatment stimulated PI promoter activity in transfection assays and a glucose-regulated element was identified (-126/-102), homologous to those previously described in other responsive genes, including l-type pyruvate kinase, S(14) and fatty acid synthase. Mutation of this element eliminated the response to glucose. This region of the ACC PI promoter was able to bind a liver nuclear factor designated ChoRF that interacts with other conserved glucose-regulated elements. This ACC PI element is also capable of conferring a strong response to glucose when linked to a heterologous promoter. We conclude that induction of ACC gene expression under lipogenic conditions in hepatocytes is mediated in part by the activation of a glucose-regulated transcription factor, ChoRF, which stimulates transcription from the PI promoter. Similar mechanisms operate on related genes permitting the coordinate induction of the lipogenic pathway.
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PMID:Glucose regulation of the acetyl-CoA carboxylase promoter PI in rat hepatocytes. 1134 83

This work was designed to study the effect of different lipid sources on hepatic lipogenic enzyme activity in rats fed ad libitum or energy-controlled diets. Male Wistar rats were fed diets containing 40% of energy as fat (olive oil, sunflower oil, palm oil, or beef tallow) for 4 wk. In experiment 1 rats had free access to food, and in experiment 2 rats were fed a controlled amount of food. In both experiments, rats fed the olive oil diets had higher activities of glucose-6-phosphate dehydrogenase, malic enzyme, fatty acid synthase, and acetyl-CoA carboxylase (P < 0.05) than rats fed the other fats. It is unlikely that this effect could be attributed to the stimulation by insulin or triiodothyronine because serum values did not differ among the groups. Enzymatic activities were positively and significantly correlated with liver triacylglycerol content, but not with serum triacylglycerol levels. No interaction between lipid source and feeding protocol was found. Oleic acid and components in olive oil other than fatty acids, such as phytosterols, may account for the effects of dietary fat on lipogenic enzyme activity.
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PMID:Differential effects of diets that provide different lipid sources on hepatic lipogenic activities in rats under ad libitum or restricted feeding. 1139 5

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.
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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.
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PMID:Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. 1144 28

Mutations in the Saccharomyces cerevisiae SNF1 gene affect a number of cellular processes, including the expression of genes involved in carbon source utilization and phospholipid biosynthesis. To identify targets of the Snf1 kinase that modulate expression of INO1, a gene required for an early, rate-limiting step in phospholipid biosynthesis, we performed a genetic selection for suppressors of the inositol auxotrophy of snf1Delta strains. We identified mutations in ACC1 and FAS1, two genes important for fatty acid biosynthesis in yeast; ACC1 encodes acetyl coenzyme A carboxylase (Acc1), and FAS1 encodes the beta subunit of fatty acid synthase. Acc1 was shown previously to be phosphorylated and inactivated by Snf1. Here we show that snf1Delta strains with increased Acc1 activity exhibit decreased INO1 transcription. Strains carrying the ACC1 suppressor mutation have reduced Acc1 activity in vitro and in vivo, as revealed by enzymatic assays and increased sensitivity to the Acc1-specific inhibitor soraphen A. Moreover, a reduction in Acc1 activity, caused by addition of soraphen A, provision of exogenous fatty acid, or conditional expression of ACC1, suppresses the inositol auxotrophy of snf1Delta strains. Together, these findings indicate that the inositol auxotrophy of snf1Delta strains arises in part from elevated Acc1 activity and that a reduction in this activity restores INO1 expression in these strains. These results reveal a Snf1-dependent connection between fatty acid production and phospholipid biosynthesis, identify Acc1 as a Snf1 target important for INO1 transcription, and suggest models in which metabolites that are generated or utilized during fatty acid biosynthesis can significantly influence gene expression in yeast.
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PMID:Inhibition of acetyl coenzyme A carboxylase activity restores expression of the INO1 gene in a snf1 mutant strain of Saccharomyces cerevisiae. 1148 11

The AMP-activated protein kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), has been found to inhibit the differentiation of 3T3-L1 adipocytes, if added at an early phase of differentiation. AICAR blocks the expression of the late adipogenic markers, fatty acid synthase and acetyl-CoA carboxylase, and of the transcription factors, C/EBPalpha and PPARgamma. It also inhibits early clonal expansion of pre-adipocytes, prevents the fall in C/EBPbeta expression during the intermediate stage of differentiation and inhibits the late phase expression of CHOP-10, an antagonist of C/EBPbeta. These data suggest a possible inhibitory role for AMPK in the process of adipose differentiation and suggest that AMPK might be a target to block adipogenesis.
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PMID:The effects of AICAR on adipocyte differentiation of 3T3-L1 cells. 1152 76

Fatty acids are synthesized de novo from acetyl-CoA and malonyl-CoA through a series of reactions mediated by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In rodents, the principal fatty acid produced by FAS is palmitic acid (16:0). Sterol regulatory element-binding proteins (SREBPs) enhance the transcription of many genes responsible for fatty acid synthesis. In transgenic mice that overexpress SREBPs in liver, the rate of fatty acid synthesis is markedly increased, owing to the activation of these biosynthetic genes, which include ATP citrate lyase, ACC, FAS, and stearoyl-CoA desaturase. The fatty acids that accumulate in livers of SREBP transgenic mice are 18 carbons rather than 16 carbons in length, suggesting that the enzymes required for the elongation of palmitic to stearic acid may be induced. Here, we report the cDNA cloning of a murine long chain fatty acyl elongase (LCE) that was identified initially by oligonucleotide array analysis of mRNA from SREBP transgenic mouse livers. LCE mRNA is highly expressed in liver and adipose tissue. The cDNA encodes a protein of 267 amino acids that shares sequence identity with previously identified very long chain fatty acid elongases. Cells that overexpress LCE show enhanced addition of 2-carbon units to C12-C16 fatty acids. We provide evidence that LCE catalyzes the rate-limiting condensing step in this reaction. The current studies suggest that mouse LCE expression is increased by SREBPs and that the enzyme is a component of the elusive mammalian elongation system that converts palmitic to stearic acid.
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PMID:Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. 1156 32


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