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)

To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of lipogenic enzymes. In the fasted state, the mRNA levels of all lipogenic enzymes were consistently low in both wild-type and SREBP-1(-/-) mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished in SREBP-1(-/-) mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refed SREBP-1(-/-) livers accompanied by an increase in nuclear SREBP-2 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these lipogenic enzymes were also strikingly lower in SREBP-1(-/-) mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.
J Biol Chem 1999 Dec 10
PMID:Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. 1058 67

Dietary polyunsaturated fatty acids (PUFA) are negative regulators of hepatic lipogenesis that exert their effects primarily at the level of transcription. Sterol regulatory element-binding proteins (SREBPs) are transcription factors responsible for the regulation of cholesterol, fatty acid, and triglyceride synthesis. In particular, SREBP-1 is known to play a crucial role in the regulation of lipogenic gene expression in the liver. To explore the possible involvement of SREBP-1 in the suppression of hepatic lipogenesis by PUFA, we challenged wild-type mice and transgenic mice overexpressing a mature form of SREBP-1 in the liver with dietary PUFA. In the liver of wild-type mice, dietary PUFA drastically decreased the mature, cleaved form of SREBP-1 protein in the nucleus, whereas the precursor, uncleaved form in the membranes was not suppressed. The decreases in mature SREBP-1 paralleled those in mRNAs for lipogenic enzymes such as fatty acid synthase and acetyl-CoA carboxylase. In the transgenic mice, dietary PUFA did not reduce the amount of transgenic SREBP-1 protein, excluding the possibility that PUFA accelerated the degradation of mature SREBP-1. The resulting sustained expression of mature SREBP-1 almost completely canceled the suppression of lipogenic gene expression by PUFA in the SREBP-1 transgenic mice. These results demonstrate that the suppressive effect of PUFA on lipogenic enzyme genes in the liver is caused by a decrease in the mature form of SREBP-1 protein, which is presumably due to the reduced cleavage of SREBP-1 precursor protein.
J Biol Chem 1999 Dec 10
PMID:A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. 1058 68

A series of chimeral genes, consisting of the yeast GAL10 promoter, yeast ACC1 leader, wheat acetyl-CoA carboxylase (ACCase; EC 6.4.1.2) cDNA, and yeast ACC1 3'-tail, was used to complement a yeast ACC1 mutation. These genes encode a full-length plastid enzyme, with and without the putative chloroplast transit peptide, as well as five chimeric cytosolic/plastid proteins. Four of the genes, all containing at least half of the wheat cytosolic ACCase coding region at the 5'-end, complement the yeast mutation. Aryloxyphenoxypropionate and cyclohexanedione herbicides, at concentrations below 10 microM, inhibit the growth of haploid yeast strains that express two of the chimeric ACCases. This inhibition resembles the inhibition of wheat plastid ACCase observed in vitro and in vivo. The differential response to herbicides localizes the sensitivity determinant to the third quarter of the multidomain plastid ACCase. Sequence comparisons of different multidomain and multisubunit ACCases suggest that this region includes part of the carboxyltransferase domain, and therefore that the carboxyltransferase activity of ACCase (second half-reaction) is the target of the inhibitors. The highly sensitive yeast gene-replacement strains described here provide a convenient system to study herbicide interaction with the enzyme and a powerful screening system for new inhibitors.
Proc Natl Acad Sci U S A 1999 Dec 07
PMID:Herbicide sensitivity determinant of wheat plastid acetyl-CoA carboxylase is located in a 400-amino acid fragment of the carboxyltransferase domain. 1058 59

When two copies of the sequences spanning -57 to -35 of the fatty acid synthase (FAS) or -64 to -41 of the ATP citrate-lyase (ACL) gene linked to a reporter gene were transfected into primary cultured hepatocytes, the reporter activities significantly increased in response to insulin/glucose treatment. In cotransfection experiments of the FAS(-57/-35) with the Sp1 or Sp3 expression vector, the reporter activities of transcription were suppressed by Sp1 and stimulated by Sp3. In the cotransfection experiments of ACL(-64/-41), the activities were suppressed by Sp1 but were unchanged by Sp3. A similar effect of Sp1 and Sp3 on transcription was seen in mRNA concentrations and enzyme activities of endogenous FAS and ACL. Moreover, the mRNA concentrations and enzyme activities of endogenous acetyl-CoA carboxylase were suppressed by Sp1 and greatly increased by Sp3. Gel mobility super shift assays using antibodies against Sp1 or Sp3 revealed the binding of the transcription factors Sp1 and Sp3 with the GC rich regions located within FAS(-57/-35) and ACL(-64/-41) genes. The formation of DNA-protein complexes was decreased in rats fed a high-carbohydrate diet in comparison with that in fasted rats, but feeding the corn oil diet inhibited this decrease. In Western immunoblotting assay, however, the amount of Sp1 and Sp3 remained unchanged in the dietary conditions. Therefore, the binding of DNA-protein complexes was not due to changes in the amount of Sp1 and Sp3 but to changes in the binding activity, suggesting that these transcription factors may be an important determinant of lipogenic enzyme expression.
FEBS Lett 1999 Dec 31
PMID:Transcriptional regulation of fatty acid synthase gene and ATP citrate-lyase gene by Sp1 and Sp3 in rat hepatocytes(1). 1061 88

A candidate gene approach was carried out on a commercial line of turkeys to assess the association between fatness variability and polymorphisms of genes involved in lipid metabolism. Four restriction fragment length polymorphisms (RFLP) were typed on the fatty acid synthase gene (MspI/pF5), on the malic enzyme gene (HindIII/em), as well as on the acetyl coenzyme A carboxylase and delta9 desaturase genes. Fatness level was estimated in vivo by an ultrasonic instrument. Fat yield was assessed after slaughter by calculating the ratio of the leg skin plus subcutaneous fat weight to the whole leg weight. Finally, the lipid content was determined by extraction from the boneless leg. The 84 female turkeys sampled were full and half-sibs born from eight sires, seven of which were heterozygous for MspI/pF5 or HindIII/em RFLP and one of which was double homozygous at these loci. The analyses of variance used to compare the genotypes at each RFLP suggested a major role associated with the fatty acid synthase gene polymorphism in the explanation of fatness variability. One homozygous genotype for MspI/pF5 was about 1.5 standard deviations leaner than the other two homozygous genotypes. An analysis of the average effects of gene substitution confirmed the association between leanness and one allele of the fatty acid synthase polymorphism. It also identified a significant association between leanness and one malic enzyme RFLP allele, congruent with a strictly additive determinism for the effect associated with this polymorphism. This experiment provided new evidence of the association between both fatty acid synthase and malic enzyme gene polymorphisms and fatness variability in turkeys.
Poult Sci 1999 Dec
PMID:Association of fatty acid synthase gene and malic enzyme gene polymorphisms with fatness in turkeys. 1062 37

Fatty acid oxidation in muscle has been reported to be diminished when insulin and glucose levels are elevated. This study was designed to determine whether activation of AMP-activated protein kinase (AMPK) will prevent inhibitory effects of insulin and glucose on the rate of fatty acid oxidation. Rat hindlimbs were perfused with medium containing 0, 0.3, or 60 nM insulin with or without 2 mM 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Glucose uptake was stimulated four- to fivefold by inclusion of insulin in the medium. Insulin attenuated the increase in AMPK caused by AICAR both in perfused hindlimbs and in isolated epitrochlearis muscles. The activation constant for citrate activation of acetyl-CoA carboxylase (ACC) was significantly increased in response to AICAR, and the increase was slightly attenuated if insulin was present in the perfusion medium. Insulin stimulated an increase in malonyl-CoA content of the muscles in the absence of AICAR. Malonyl-CoA was decreased to approximately the same value in AICAR-perfused muscle, regardless of insulin concentration. Muscle glucose 6-phosphate and citrate were significantly increased in response to AICAR and insulin. The rate of palmitate oxidation tended to decrease in response to insulin and in the absence of AICAR. AICAR increased palmitate oxidation to approximately the same level regardless of the insulin concentration or the rate of glucose uptake into the muscle. The rate of palmitate oxidation showed a curvilinear relationship as a function of muscle malonyl-CoA content, with half-maximal inhibition at approximately 0.6 nmol/g. We conclude that AMPK activation can prevent high rates of glucose uptake and glycolytic flux from inhibiting palmitate oxidation in predominantly fast-twitch muscle under these conditions.
J Appl Physiol (1985) 2000 Dec
PMID:Insulin stimulation of glucose uptake fails to decrease palmitate oxidation in muscle if AMPK is activated. 1109 May 99

A lipolytic domain (AOD9401) of human growth hormone (hGH) which resides in the carboxyl terminus of the molecule and contains the amino acid residues 177-191, has been synthesized using solid-phase peptide synthesis techniques. AOD9401 stimulated hormone-sensitive lipase and inhibited acetyl coenzyme A carboxylase (acetyl CoA carboxylase) in isolated rat adipose tissues, in a similar manner to the actions of the intact hGH molecule. The synthetic lipolytic domain mimicked the effect of the intact growth hormone on diacylglycerol release in adipocytes. Chronic treatment of obese Zucker rats with AOD9401 for 20 days reduced the body weight gain of the animals, and the average cell size of the adipocytes of the treated animals decreased from 110 to 80 microm in diameter. Unlike hGH, synthetic AOD9401 did not induce insulin resistance or glucose intolerance in the laboratory animals after chronic treatment. The results suggest that AOD9401 has the potential to be developed into a therapeutic agent for the control of obesity.
J Mol Endocrinol 2000 Dec
PMID:Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. 1111 8

We have characterized the expression of potential acetyl-CoA-generating genes (acetyl-CoA synthetase, pyruvate decarboxylase, acetaldehyde dehydrogenase, plastidic pyruvate dehydrogenase complex and ATP-citrate lyase), and compared these with the expression of acetyl-CoA-metabolizing genes (heteromeric and homomeric acetyl-CoA carboxylase). These comparisons have led to the development of testable hypotheses as to how distinct pools of acetyl-CoA are generated and metabolized. These hypotheses are being tested by combined biochemical, genetic and molecular biological experiments, which is providing insights into how acetyl-CoA metabolism is regulated.
Biochem Soc Trans 2000 Dec
PMID:Molecular biology of acetyl-CoA metabolism. 1117 Nov 36

ATP citrate lyase (ACL) catalyses the ATP-dependent reaction between citrate and CoA to form oxaloacetate and acetyl-CoA. Our molecular characterizations of the cDNAs and genes coding for the Arabidopsis ACL indicate that the plant enzyme is heteromeric, consisting of two dissimilar subunits. The A subunit is homologous to the N-terminal third of the animal ACL, and the B subunit is homologous to C-terminal two-thirds of the animal ACL. Using both ACL-A- and ACL-B-specific antibodies and activity assays we have shown that ACL is located in the cytosol, and is not detectable in the plastids, mitochondria or peroxisomes. During seed development, ACL-A and ACL-B mRNA accumulation is co-ordinated with the accumulation of the cytosolic homomeric acetyl-CoA carboxylase mRNA. Antisense Arabidopsis plants reduced in ATP citrate lyase activity show a complex phenotype, with miniaturized organs, small cell size, aberrant plastid morphology and reduced cuticular wax. Our results indicate that ACL generates the cytosolic pool of acetyl-CoA, which is the substrate required for the biosynthesis of a variety of phytochemicals, including cuticular waxes and flavonoids.
Biochem Soc Trans 2000 Dec
PMID:Molecular biology of cytosolic acetyl-CoA generation. 1117 Nov 37

De novo fatty acid biosynthesis occurs predominantly in plastids. The committed step for this pathway is the production of malonyl-CoA catalysed by acetyl-CoA carboxylase (ACCase). In most plants, plastidial ACCase is a multisubunit complex minimally comprised of four polypeptides, which catalyse two reactions. In the simple oilseed plant, Arabidopsis thaliana, two cDNAs encoding biotin carboxyl carrier protein (BCCP) isoforms have been identified. The remaining three subunits of ACCase appear to be single gene members in A. thaliana [Mekhedov, Martinez de Ilarduya and Ohlrogge (2000) Plant Physiol. 122, 389-401]. Transcript and protein analyses indicate that BCCP isoform 1 is constitutively expressed while isoform 2 is predominantly expressed in developing seeds. The apparent masses of constitutive and seed-enriched BCCP isoforms agree with the apparent masses of recombinantly expressed isoforms 1 and 2, respectively. In a related oilseed, Brassica napus, multiple putative BCCP polypeptides were also observed in developing seeds. The presence of a divergent class of BCCP genes in A. thaliana and B. napus, coincident with appropriately sized biotin-containing proteins expressed specifically in developing seeds, suggests that these BCCPs play an evolutionarily conserved role in oil deposition.
Biochem Soc Trans 2000 Dec
PMID:Biotin carboxyl carrier protein isoforms in Brassicaceae oilseeds. 1117 Nov 38


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