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)

Diabetic and nondiabetic rats were used to ascertain if dietary polyunsaturated fats inhibited hepatic acetyl-CoA carboxylase and fatty acid synthetase in insulin-insufficient rats as had been previously shown for normal rats. Male rats were rendered diabetic (400-600) mg glucose/100 mL blood) with streptozotocin and were fed a high fructose fat-free diet. Safflower oil or palmitate (or tallow) was added to the basal fructose diet at a level to supply 12,24 or 36% additional digestible energy. Compared with normal rats, diabetic rats had significantly lower hepatic fatty acid biosynthesis, but the proportion of acetyl-CoA carboxylase expressing catalytic activity as determined by the avidin-inactivation technique was unaffected by diabetes. Diabetes did not lower the maximal maximal activities of carboxylase and fatty acid synthetase. Moreover, the activities of these enzymes greatly exceeded the rate of fatty acid synthesis. At all levels of fat supplementation, the high linoleate safflower oil consistently resulted in a 50% lower rate of fatty acid biosynthesis than did comparable levels of tallow or palmitate. Safflower oil was also a more effective suppressor of the activities of acetyl-CoA carboxylase and fatty acid synthetase than the saturated fats. Our data suggest that the greater inhibition of hepatic fatty acid biosynthesis by polyenoic fatty acids is an insulin-independent mechanism.
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PMID:Inhibition of liver lipogenesis by dietary polyunsaturated fat in severely diabetic rats. 287 68

Feeding lactating rats on high-fat cheese crackers in addition to laboratory chow increased the dietary intake of fat from 2 to 20% of the total weight of food eaten and decreased mammary-gland lipogenesis in vivo by approx. 50%. This lipogenic inhibition was also observed in isolated mammary acini, where it was accompanied by decreased glucose uptake. These inhibitions were completely reversed by incubation with insulin. Insulin had no effect on the rate of glucose transport into acini, nor on pyruvate dehydrogenase activity as estimated by the accumulation of pyruvate and lactate, suggesting that these are not the sites of lipogenic inhibition. Insulin stimulated the incorporation of [1-14C]acetate into lipid in acini from high-fat-fed rats. In the presence of alpha-cyanohydroxycinnamate, a potent inhibitor of mitochondrial pyruvate transport, and with glucose as the sole substrate, neither [1-14C]glucose incorporation into lipid nor glucose uptake were stimulated by insulin. Insulin did stimulate the incorporation of [1-14C]acetate into lipid in the presence of alpha-cyanohydroxycinnamate, and this was accompanied by an increase in glucose uptake by the acini. This indicated that increased glucose uptake was secondary to the stimulation of lipogenesis by insulin, which therefore must occur via activation of a step in the pathway distal to mitochondrial pyruvate transport. Insulin stimulated acetyl-CoA carboxylase activity measured in crude extracts of acini from high-fat-fed rats, restoring it to values close to those of chow-fed controls. The effects of insulin on acetyl-CoA carboxylase activity and lipogenesis were not antagonized by adrenaline or dibutyryl cyclic AMP.
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PMID:Insulin activation of lipogenesis in isolated mammary acini from lactating rats fed on a high-fat diet. Evidence that acetyl-CoA carboxylase is a site of action. 288 93

9-Oxononanoic acid, which is one of the major products of the autoxidation of linoleic acid, was administered orally to rats and its effect on hepatic lipid metabolism was investigated. The de novo synthesis of fatty acids was strongly reduced 30 h after the administration of 100 mg of 9-oxononanoic acid as compared to that in the saline-administered group. Activity of acetyl-CoA carboxylase decreased by 60% and the activity of carnitine palmitoyltransferase increased by 35% in the test group. The level of triacylglycerols in serum was low and the level of free fatty acids remained unchanged. Thus, the administration of 9-oxononanoic acid decreased hepatic lipogenesis. It is generally believed that the reduction in lipogenesis is facilitated by a decrease in the NADPH level. The ratio of NADPH/NADP in the test group, however, became high as compared to that in the control group, and the activities of glucose 6-phosphate and isocitrate dehydrogenases increased. On the other hand, the levels of CoA derivatives, especially long-chain acyl-CoA, were higher in the test group than in the control. Therefore, the reduction of hepatic lipogenesis in the 9-oxononanoic acid group could be attributed to the inhibition of acetyl-CoA carboxylase by the accumulated long-chain acyl-CoA.
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PMID:Effect of orally administered 9-oxononanoic acid on lipogenesis in rat liver. 289 34

A high rate of lipogenesis in obese mice plays a major role in their excessive deposition of body lipid. Inhibition of lipogenesis may decrease their obesity. Therefore, we have investigated the effects of sodium 2-n-pentadecyl-benzimidazole-5-carboxylate (M & B 35347B), an inhibitor of acetyl-CoA carboxylase, on in-vivo lipogenesis in obese and lean mice. It significantly inhibited hepatic cholesterol and fatty acid synthesis, measured using 3H2O, in both lean and obese mice, with or without a glucose load. Brown adipose tissue (scapular) lipogenesis was decreased by M & B 35347B in obese mice but not in lean mice. In white adipose tissue, M & B 35347B did not affect the rates of lipogenesis in either scapular white, inguinal or epididymal depots of obese mice, or the inguinal and scapular white depot of lean mice. However, it doubled lipogenesis in the epididymal fat pad of lean mice. After a glucose load, lipogenesis in the lean epididymal fat pad was not inhibited but that in the inguinal depot was. M & B 35347B inhibited acetyl CoA carboxylase of adipose tissue in vitro but only a small inhibition was detected after in-vivo treatment. These different responses according to type of mouse, treatment and tissue site appear to stem from differences in inhibitor concentration and the importance of acetyl CoA carboxylase as the rate-limiting enzyme of lipogenesis. The weight gain of obese mice dosed orally (200 mg M & B 35347B/kg daily) for 60 days was unaffected and they continued to deposit excess body fat. This presumably occurred because of the lack of inhibition of fatty acid synthesis in white adipose tissue.
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PMID:Effect of sodium 2-n-pentadecyl-benzimidazole-5-carboxylate (M & B 35347B), an inhibitor of acetyl-CoA carboxylase, on lipogenesis and fat deposition in obese hyperglycaemic (ob/ob) and lean mice. 289 66

Rat hepatocytes in monolayer culture were utilized to determine if the decrease in glucose-6-phosphate dehydrogenase (G6PD) activity resulting from the ingestion of fat can be mimicked by the addition of fatty acids to a chemically, hormonally defined medium. G6PD activity in cultured hepatocytes was induced several-fold by insulin. Dexamethasone or T3 did not amplify the insulin induction of G6PD. Glucose alone increased G6PD activity in cultured hepatocytes from fasted donors by nearly 500%. Insulin in combination with glucose induced G6PD an additional two-fold. The increase in G6PD activity caused by glucose was greater in hepatocytes isolated from 72 hr-fasted rats as compared to fed donor rats. Such a response was reminiscent of the "overshoot" phenomenon in which G6PD activity is induced well above the normal level by fasting-refeeding rats a high glucose diet. Addition of linoleate to the medium resulted in a significant suppression of insulin's ability to induce G6PD, but linoleate had no effect on the induction of G6PD activity by glucose alone. A shift to the right in the insulin-response curve for the induction of G6PD also was detected for the induction of malic enzyme and acetyl-CoA carboxylase. Arachidonate (0.25 mM) was a significantly more effective inhibitor of the insulin action than linoleate was. Apparently rat hepatocytes in monolayer culture can be utilized as a model to investigate the molecular mechanism by which fatty acids inhibit the production of lipogenic enzymes. In part, this mechanism of fatty acid inhibition involves desensitization of hepatocytes to the lipogenic action of insulin.
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PMID:Free fatty acid inhibition of the insulin induction of glucose-6-phosphate dehydrogenase in rat hepatocyte monolayers. 289 10

Administration of ethanol as part of a nutritionally adequate liquid diet to female Wistar rats was found to depress markedly incorporation of labelled glucose into adipose-tissue acylglycerol fatty acids. Similar results with labelled pyruvate and acetate suggested inhibition of the fatty-acid-synthesis pathway at, or distal to, the acetyl-CoA carboxylase step. Activities of acetyl-CoA carboxylase and fatty acid synthetase were markedly lower in ethanol-fed animals. The activity of another lipogenic enzyme, phosphatidate phosphohydrolase, was not affected by chronic ethanol feeding. These findings suggest that chronic ethanol administration has marked effects on adipose-tissue lipogenesis.
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PMID:Chronic ethanol administration depresses fatty acid synthesis in rat adipose tissue. 290 3

1. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) stimulates fatty acid synthesis from glucose in isolated adipocytes with a half-maximal effect at 0.72 microM. In seven batches of cells, the maximal effects of TPA and insulin were 8.5 +/- 1.1-fold and 27.1 +/- 2.1-fold respectively. Insulin also stimulated fatty acid synthesis from acetate 8.9 +/- 0.5-fold (three experiments), but TPA did not significantly increase fatty acid synthesis from this precursor. 2. In contrast to insulin, TPA treatment of isolated adipocytes did not produce an activation of acetyl-CoA carboxylase which was detectable in crude cell extracts. 3. The total phosphate content of acetyl-CoA carboxylase, isolated from adipocytes in the presence of protein phosphatase inhibitors, was estimated by 32P-labelling experiments to be 2.6 +/- 0.1 (5), 3.4 +/- 0.2 (5), and 3.8 +/- 0.2 (3) mol/mol subunit for enzyme from control, insulin- and TPA-treated cells respectively. Insulin and TPA stimulated phosphorylation within the same two tryptic peptides. 4. Purified acetyl-CoA carboxylase is phosphorylated in vitro by protein kinase C at serine residues which are recovered in three tryptic peptides, i.e. peptide T1, which appears to be identical with the peptide Ser-Ser(P)-Met-Ser-Gly-Leu-His-Leu-Val-Lys phosphorylated by cyclic-AMP-dependent protein kinase, and peptides Ta and Tb, which have the sequences Ile-Asp-Ser(P)-Gln-Arg and Lys-Ile-Asp-Ser(P)-Gln-Arg respectively, and which appear to be derived from a single site by alternative cleavages. None of these correspond to the peptides whose 32P-labelling increase in response to insulin or TPA. Peptides Ta/Tb are not significantly phosphorylated in isolated adipocytes, even after insulin or TPA treatment. Peptide T1 is phosphorylated in isolated adipocytes, but this phosphorylation is not altered by insulin or TPA. 5. These results show that TPA mimics the effect of insulin on phosphorylation, but not activation, of acetyl-CoA carboxylase, i.e. that these two events can be dissociated. In addition, phorbol ester stimulates phosphorylation of acetyl-CoA carboxylase in isolated adipocytes, but this is not catalyzed directly by protein kinase C, and acetyl-CoA carboxylase does not appear to be a physiological substrate for this kinase.
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PMID:Insulin and phorbol ester stimulate phosphorylation of acetyl-CoA carboxylase at similar sites in isolated adipocytes. Lack of correspondence with sites phosphorylated on the purified enzyme by protein kinase C. 290 Jan 39

Activities (mumol X min-1 X g liver) and zonal distributions of key enzymes of carbohydrate metabolism were studied in livers of streptozotocin-diabetic rats and compared to the values in alloxan-diabetes. Streptozotocin led to a non-ketotic diabetes with blood glucose being increased by more than fivefold but ketone bodies being in the normal range, while alloxan produced a ketotic diabetes with blood glucose, acetoacetate and beta-hydroxybutyrate being elevated by more than fivefold. Portal insulin was decreased to about 20% in streptozotocin- and more drastically to about 7% in alloxan-diabetes. Conversely, portal glucagon was increased in the two states to about 250% and 180%, respectively. The glucogenic key enzyme phosphoenolpyruvate carboxykinase (PEPCK) was enhanced in streptozotocin- and alloxan-diabetes to over 300%, while the glycolytic pyruvate kinase L (PKL) was lowered to 65% and 80%, respectively. The normal periportal to perivenous gradient of PEPCK of about 3:1, as measured in microdissected tissue samples, was maintained with elevated activities in the two zones. The normal periportal to perivenous gradient of PKL of 1:1.7 was diminished with lowered activities in the two zones. The glucogenic glucose-6-phosphatase (G6Pase) was increased in streptozotocin- and alloxan-diabetes to 130% and 140%, respectively, while the glucose utilizing glucokinase (GK) was decreased to 60% and 50%, respectively. The normal periportal to perivenous gradient of G6Pase, demonstrated histochemically, remained unaffected. Carnitine palmitoyltransferase (CPT) was increased to over 190% and acetyl-CoA carboxylase (ACC) was decreased to 60% in streptozotocin, non-ketotic diabetes, while the two enzymes were altered more drastically to 400% and 50%, respectively, in alloxan, ketotic diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gluconeogenic-glycolytic capacities and metabolic zonation in liver of rats with streptozotocin, non-ketotic as compared to alloxan, ketotic diabetes. 302 62

Lipid metabolism in hormone-dependent (HD) GR mouse mammary tumors was compared to that in hormone-independent (HI) tumors and normal mammary tissues. HD tumors, like normal mammary tissue but unlike HI tumors, synthesized medium-chain-length fatty acids (MCFA). However, when treated with hormones (estrone and progesterone), the HI tumors were induced to produce MCFA. The activity of thioesterase II correlated positively with the synthesis of MCFA and was influenced by the hormones administered. The activities of NADP+-linked malate dehydrogenase, citrate lyase, acetyl-CoA carboxylase, and fatty acid synthetase, although lower in tumors than in normal glands, were not different in HD as compared to HI tumors. Whereas the predominating lipids synthesized in normal glands were triglycerides, phospholipids comprised about half of the lipid synthesized in the tumors, with no difference between HD and HI tumors. The conversion of D-[U-14C]glucose to 14CO2 was higher in HD tumors than in HI tumors but increased in HI tumors treated with hormones in vivo. By a comparison of the 14CO2 produced from D-[1-14C]glucose and from D-[6-14C]glucose in the presence and absence of an electron acceptor (methylene blue), it was demonstrated that regeneration of NADP+ from NADPH was a rate-limiting step for the pentose phosphate pathway in the tumors. Hence, while differences in the lipid metabolism can be demonstrated between HD and HI GR mouse mammary tumors, some of the changes are due to the hormone treatment rather than to a specific alteration in the tumor itself.
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PMID:Lipid metabolism and enzyme activities in hormone-dependent and hormone-independent mammary adenocarcinoma in GR mice. 308 11

The disposition of topical dimethylacetylenedicarboxylate (DMAD) in tissue and its effect on glucose metabolism were studied in vivo, using skin grafted athymic nude mice, and in vitro, using excised pig skin. [14C]DMAD that penetrated skin grafts was distributed throughout the body. At 24 hr, the liver contained 15.62% of the applied dose. The kidneys, lungs, brain, and the heart contained 12.73, 5.61, 0.36, and 3.24% of the dose, respectively. One hour postapplication, DMAD markedly decreased [U-14C]glucose oxidation and the syntheses of fatty acids and glycogen in the livers and skin grafts. Similar effects were observed in excised pig skin. In addition, the activities of hepatic glucose-6-phosphate dehydrogenase, isocitric and NADP-malic dehydrogenase, and acetyl-CoA carboxylase were significantly reduced in DMAD-treated mice. In contrast, no effect was observed on the activity of glucokinase. The data indicate that DMAD rapidly penetrates the skin and causes aberrations in the activities of the glycogenic, lipogenic, and tricarboxylic acid metabolic pathways.
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PMID:Metabolic alterations induced by topical dimethylacetylenedicarboxylate. 339 97


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