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)

Evidence is presented that rat liver microsomal fatty acid chain elongation synthesis and desaturation, as well as acetyl-CoA carboxylase and fatty acid synthetase, are strongly influenced by thyroid hormone level. Conversely, the fatty acid chain elongation system in mitochondria, unlike the oxidative capacity of palmitate, NADH, succinate and malate, does not seem significantly affected by the thyrotoxic state. In triiodothyronine-induced or thyroxine-induced hyperthyroidism, rat liver acetyl-CoA carboxylase, fatty acid synthetase and microsomal chain elongation and desaturation reactions are not greatly affected after the first 10 days of treatment, while after longer intervals a respective increase in these activities is shown of up to 87, 116 and 65% after 22 days. In propylthiouracil-induced hypothyroidism, all the above synthetic activities are strongly reduced immediately after three days of drug administration and diminished no further following longer periods. Although the pattern of synthesized fatty acids in the thyrotoxic state is similar to that obtained from normal subcellular rat fractions, the esterification process of fatty acids in microsomal lipids appears to be slightly inhibited in hypothyroid rats and increased following triiodothyronine or thyroxine administration. Finally, a reduction in the hepatic cyclic AMP level of about 41% is reported after 19 days of triiodothyronine-administration to rats. On the basis of the observed insensitivity of the mitochondrial fatty acid chain elongation system to the thyrotoxic state, a tentative interpretation of its role in the hepatic cell is postulated.
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PMID:Effect of thyroid hormones on microsomal fatty acid chain elongation synthesis in rat liver. 1 55

The influence of thyroid hormones on lipid biosynthesis was studied after administration of L-thyroxine to rats for 5 days. Their weights remained the same as those of control animals, despite an approximately 3-fold increment in plasma L-thyroxine and L-triiodothyronine concentrations. The activity of acetyl-CoA carboxylase and fatty acid synthetase as well as incorporation of tritium into fatty acids were depressed significantly in epididymal adipose tissue and enhanced significantly in livers of thyroxine-treated rats. Using antibodies specific against rat liver fatty acid synthetase, it was determined that the changes in activity of this multienzymic complex were due to alterations in amount of enzyme protein. In the presence of optimal concentrations of fatty acids, radioactive sn-glycero-3-phosphate, and co-substrates, total glycerolipid synthesis (defined in this study as the sum of newly formed radioactive mono- and diacyl-sn-glycero-3-phosphate, diglyceride, and triglyceride) was decreased significantly in adipose tissue and increased in liver and heart. Thus, administration of thyroid hormone results in tissue-specific alterations in lipid biosynthesis which, at least in the case of fatty acid synthetase, are due to changes in enzyme protein content.
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PMID:Effects of thyroid hormones on enzymes involved in fatty acid and glycerolipid synthesis. 23 12

We have examined the activity of three lipogenic enzymes [malic enzyme (ME), glucose-6-phosphate dehydrogenase (G-6-PD), and acetyl coenzyme A (CoA) carboxylase], the activity of the mitochondrial FAD-dependent alpha-glycerolphosphate dehydrogenase (alpha-GPD), and the mitochondrial concentration of uncoupling protein (UCP) in brown adipose tissue (BAT) of euthyroid and hypothyroid rats, both at room temperature and in response to acute cold stress. These enzymes and UCP are important for the thermogenic response of BAT in adaptation to cold. The basal level of the lipogenic enzymes was normal or slightly elevated in hypothyroid rats maintained at 23 degrees C, but the levels of alpha-GPD and UCP were markedly reduced. Forty-eight hours at 4 degrees C resulted in an increase in the activity of G-6-PD, acetyl-CoA carboxylase, and alpha-GPD and in the concentration of UCP both in euthyroid and hypothyroid animals, but the levels reached were invariably less in hypothyroid animals, indicating that thyroid hormone is necessary for a full metabolic response of BAT under maximal demands. Of all variables measured, the most affected was UCP (only one-fifth of the response of euthyroid rats to cold) followed by alpha-GPD (approximately 50% the euthyroid response). The administration of replacement doses of triiodothyronine (T3) to hypothyroid rats for 5-7 days did not normalize any of the BAT responses, whereas the replacement of thyroxine (T4) for only 2 days sufficed to normalize them all. This effect of T4 was abolished by preventing its conversion to T3 with iopanoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Optimal response of key enzymes and uncoupling protein to cold in BAT depends on local T3 generation. 363 Dec 56

Vanadium is a potent insulinomimetic agent. In vivo, its blood glucose lowering action in insulin-deficient diabetic rats is associated with corrected expression of genes involved in hepatic glucose metabolism. In this study, we investigated whether vanadate treatment also reverses the impaired expression of genes coding for key enzymes of lipogenesis in diabetic liver and white adipose tissue. Oral administration of vanadate to streptozotocin-rats caused a 55% fall in plasma glucose levels after feeding without modifying low insulinaemia. It also partially corrected the low thyroid hormone concentrations. In untreated diabetic animals, hepatic mRNA levels of acetyl-CoA carboxylase and fatty acid synthase were reduced by more than 80 and 90%, respectively, in close correlation with changes in enzyme activities. Three weeks of vanadate treatment totally restored acetyl-CoA carboxylase mRNA and partially restored fatty acid synthase mRNA (71% of control levels). The activities of both lipogenic enzymes were increased 3.5 to 4-fold, to reach 45 to 65% of control values. By contrast, in white adipose tissue, vanadate modified neither expression nor activity of both lipogenic enzymes, which remained blunted (< 10% of control levels). In conclusion, vanadate treatment partially restores the activities of two key lipogenic enzymes in liver, but not in white adipose tissue, of diabetic rats. This correction results from a reversal of impaired pre-translational regulatory mechanisms possibly mediated by an improvement of thyroid function and a selective restoration of liver glycolytic flux.
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PMID:Tissue-specific correction of lipogenic enzyme gene expression in diabetic rats given vanadate. 786 78

Thyroid hormone regulates lipogenesis differently in rat liver and brown adipose tissue (BAT). In the hypothyroid state, lipogenesis is suppressed in liver but enhanced in BAT. Here we investigated the mechanisms underlying increased lipogenesis in hypothyroid BAT. Housing the animals at 28 degrees C decreased lipogenesis in hypothyroid BAT to euthyroid levels. Denervation resulted in a 90% reduction in lipogenesis in hypothyroid BAT such that levels were lower than in euthyroid tissue. Thyroid hormone treatment of hypothyroid rats stimulated fatty acid synthesis in denervated BAT, as in liver, but decreased it in intact BAT. Steady-state levels of mRNA encoding acetyl-CoA carboxylase, fatty-acid synthase, and spor 14 were measured in similar animals by Northern analysis. The expression of these mRNAs mirrored the lipogenic data, showing that both thyroid hormone and the sympathetic nervous system work at a pretranslational level in this tissue. These data suggest that the increased BAT lipogenesis found with hypothyroidism is mediated by the sympathetic nervous system to counter the reduction in metabolic rate in these animals.
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PMID:Regulation of brown adipose tissue lipogenesis by thyroid hormone and the sympathetic nervous system. 836 94

Enhanced long chain fatty acid synthesis may occur in breast cancer, where it is necessary for tumor growth and predicts a poor prognosis. "Spot 14" (S14) is a carbohydrate- and thyroid hormone-inducible nuclear protein specific to liver, adipose, and lactating mammary tissues that functions to activate genes encoding the enzymes of fatty acid synthesis. Amplification of chromosome region 11q13, where the S14 gene (THRSP) resides, also predicts a poor prognosis in breast tumors. We localized the S14 gene between markers D11S906 and D11S937, at the telomeric end of the amplified region at 11q13, and found that it was amplified and expressed in breast cancer-derived cell lines. Moreover, concordant expression of S14 and a key lipogenic enzyme (acetyl-CoA carboxylase) in a panel of primary breast cancer specimens strongly supported a role for S14 as a determinant of tumor lipid metabolism. S14 expression provides a pathophysiological link between two prognostic indicators in breast cancer: enhanced lipogenesis and 11q13 amplification.
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PMID:The "Spot 14" gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers: implications for control of tumor metabolism. 961 26

The acetyl-CoA carboxylase-alpha gene has two promoters, PI and PII. A variety of mRNA products result from this gene, depending on promoter usage and splicing events. We have investigated thyroid hormone regulation of acetyl-CoA carboxylase-alpha gene expression, using the reverse-transcription polymerase chain reaction with PI- or PII-specific primers. RNA was extracted from a range of tissues taken from hypo-, eu-, or hyperthyroid rats. PII-generated products were found in all tissues examined at similar levels and were not affected by thyroid state. Products derived from PI were also widely found but with more variable levels of expression. PI mRNAs were reduced in hypo- and elevated in hyperthyroid livers. In brown adipose tissue, more PI products were found in hypothyroid animals. Thus, thyroid hormone regulates the activity of the acetyl-CoA carboxylase PI promoter to influence fatty acid synthesis in a tissue-specific manner.
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PMID:Thyroid hormone regulates the acetyl-CoA carboxylase PI promoter. 973 Dec 1

AMP-activated protein kinase (AMPK) consists of three subunits: alpha, beta, and gamma. Two isoforms exist for the alpha-subunit (alpha(1) and alpha(2)), two for the beta-subunit (beta(1) and beta(2)), and three for the gamma-subunit (gamma(1), gamma(2), and gamma(3)). Although the specific roles of the beta- and gamma-subunits are not well understood, the alpha-subunit isoforms contain the catalytic site and also the phosphorylation/activation site for the upstream kinase. This study was designed to determine the role of thyroid hormones in controlling expression levels of these AMPK subunits and of one downstream target, acetyl-CoA carboxylase (ACC), in muscle. AMPK subunit and ACC levels were determined by Western blots in control rats, in rats given 0.01% propylthiouracil (PTU) in drinking water for 3 wk, and in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 1 or 3 wk. In gastrocnemius muscle, all isoforms of AMPK subunits were significantly increased in rats given thyroid hormones for 3 wk vs. those treated with PTU. Similar patterns were seen in individual muscle types. Expression of muscle ACC was also significantly increased in response to 3 wk of treatment with excess thyroid hormones. Muscle content of malonyl-CoA was elevated in PTU-treated rats and depressed in thyroid hormone-treated rats. These data provide evidence that skeletal muscle AMPK subunit and ACC expression is partially under the control of thyroid hormones.
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PMID:Effects of thyroid state on AMP-activated protein kinase and acetyl-CoA carboxylase expression in muscle. 1243 37

Evidence is accumulating for roles of AMP-activated protein kinase (AMPK) in controlling glucose uptake, fatty acid oxidation and gene expression in skeletal muscle. Relatively little is known, however, about the control of expression of the AMPK subunit isoforms. Marked differences are noted in subunit expression as a function of muscle fibre type. Expression of the gamma3 subunit isoform increases in fast-twitch red fibres of the rat in response to training. All subunit isoforms are expressed to a lesser extent in rats treated with propylthiouracil (PTU; an inhibitor of thyroid hormone synthesis) for 3 weeks compared with rats given excess thyroid hormones for 3 weeks. An approx. 2-fold increase in acetyl-CoA carboxylase was observed in gastrocnemius of hyperthyroid rats compared with experimentally hypothyroid rats. Thyroid state therefore appears to be one important factor controlling expression of these proteins in skeletal muscle.
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PMID:Long-term regulation of AMP-activated protein kinase and acetyl-CoA carboxylase in skeletal muscle. 1254 81

Hyroid hormone stimulates hepatic lipogenesis in the rat by increasing the expression of relevant genes, including acetyl-CoA carboxylase and fatty acid synthase. S14 mRNA, which encodes a protein thought to be involved in lipogenesis, responds in parallel. The effects of thyroid hormone on lipogenesis in white and brown adipose tissue are less clear, and may be complicated by indirect effects of the hormone. Rat white and brown preadipocytes were therefore isolated, grown to confluence, and used to test direct effects of thyroid hormone, insulin, and glucose. Lipogenesis was assessed by tritiated water incorporation, and acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and S14 mRNAs were measured by Northern analysis. Insulin (1 nM) increased lipogenesis about 9-fold in both white and brown adipocytes. Similar increases were seen in the levels of the three mRNAs. Thyroid hormone (1 microM) stimulated lipogenesis and acetyl-CoA carboxylase, fatty acid synthase, and S14 mRNA levels up to 2-fold in both types of adipocyte in the presence or absence of insulin. A high carbohydrate level (25 mM glucose) had no effect on lipogenesis compared to a low carbohydrate level (5 mM glucose) in white and brown adipocytes. There was no synergistic effect on lipogenesis by the combination of thyroid hormone and high carbohydrate level in both types of adipocytes. These experiments have shown that T3 has small, direct stimulatory effects on lipogenesis in adipocytes. These effects are seen at a pre-translational level, through the coordinate induction of ACC, FAS, and S14 mRNAs. Although lipogenic rates were usually higher in brown adipocytes than white adipocytes, very similar patterns of regulation were seen in the two cell types. These data support the idea that the divergent results seen concerning T3 regulation of the lipogenic pathway in both brown and white adipose tissue in vivo arise from secondary effects of the alteration of thyroid status.
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PMID:Hormonal and nutritional regulation of lipogenic enzyme mRNA levels in rat primary white and brown adipocytes. 1288 95


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