scholarly journals Genomic distribution of three promoters of the bovine gene encoding acetyl-CoA carboxylase α and evidence that the nutritionally regulated promoter I contains a repressive element different from that in rat

2001 ◽  
Vol 358 (1) ◽  
pp. 127-135 ◽  
Author(s):  
Jianqiang MAO ◽  
Sagrario MARCOS ◽  
Scott K. DAVIS ◽  
Jay BURZLAFF ◽  
Hans-Martin SEYFERT
Keyword(s):  
De Novo ◽  
Bos Taurus ◽  
Mammalian Species ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Gene Encoding ◽  
Bovine Gene ◽  
Rapid Amplification ◽  
The Individual ◽  
Different Origins

The enzyme acetyl-CoA carboxylase α (ACC-α) is rate-limiting for the synthesis of long-chain fatty acids de novo. As a first characterization of the bovine gene encoding this enzyme, we established the entire bovine ACC-α cDNA sequence (7041bp) and used experiments with 5′ rapid amplification of cDNA ends to determine the heterogeneous composition of 5′ untranslated regions, as expressed from three different promoters (PI, PII and PIII). The individual locations of these promoters have been defined within an area comprising 35kbp on Bos taurus chromosome 19 (‘BTA19’), together with the segmentation of the first 14 exons. Primer extension analyses reveal that the nutritionally regulated PI initiates transcription from at least four sites. PI transcripts are much more abundant in adipose and mammary-gland tissues than in liver or lung. A 2.6kb promoter fragment drives the expression of reporter genes only weakly in different model cells, irrespective of stimulation with insulin or dexamethasone. Thus bovine PI is basically repressed, like its analogue from rat. Finely graded deletions of PI map two separate elements, which have to be present together in cis to repress bovine PI. The distal component resides within a well-preserved Art2 retroposon element. Thus sequence, structure and evolutionary origin of the main repressor of PI in bovines are entirely different from its functional counterpart in rat, which had been identified as a (CA)28 microsatellite. We show that, in different mammalian species, unrelated genome segments of different origins have been recruited to express as functionally homologous PI the ancient and otherwise highly conserved ACC-α-encoding gene.

scholarly journals Acetyl-CoA Carboxylase 2−/− Mutant Mice are Protected against Fatty Liver under High-fat, High-carbohydrate Dietary and de Novo Lipogenic Conditions

2012 ◽  
Vol 287 (15) ◽  
pp. 12578-12588 ◽  
Author(s):  
Lutfi Abu-Elheiga ◽  
Hongmei Wu ◽  
Ziwei Gu ◽  
Rubin Bressler ◽  
Salih J. Wakil
Keyword(s):  
Fatty Liver ◽  
De Novo ◽  
Mutant Mice ◽  
Acetyl Coa Carboxylase ◽  
Wild Type ◽  
High Fat ◽  
Acetyl Coa ◽  
High Carbohydrate ◽  
Ppar Γ ◽  
Hepatic Fat

Hepatic fat accumulation resulting from increased de novo fatty acid synthesis leads to hepatic steatosis and hepatic insulin resistance. We have shown previously that acetyl-CoA carboxylase 2 (Acc2−/−) mutant mice, when fed a high-fat (HF) or high-fat, high-carbohydrate (HFHC) diet, are protected against diet-induced obesity and maintained whole body and hepatic insulin sensitivity. To determine the effect of an ACC2 deletion on hepatic fat metabolism, we studied the regulation of the enzymes involved in the lipogenic pathway under Western HFHC dietary and de novo lipogenic conditions. After completing the HFHC regimen, Acc2−/− mutant mice were found to have lower body weight, smaller epididymal fat pads, lower blood levels of nonesterified fatty acids and triglycerides, and higher hepatic cholesterol than wild-type mice. Significant up-regulation of lipogenic enzymes and an elevation in hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) protein were found in Acc2−/− mutant mice under de novo lipogenic conditions. The increase in lipogenic enzyme levels was accompanied by up-regulation of the transcription factors, sterol regulatory element-binding proteins 1 and 2, and carbohydrate response element-binding protein. In contrast, hepatic levels of the PPAR-γ and PPAR-α proteins were significantly lower in the Acc2−/− mutant mice fed an HFHC diet. When compared with wild-type mice fed the same diet, Acc2−/− mutant mice exhibited a similar level of AKT but with a significant increase in pAKT. Hence, deleting ACC2 ameliorates the metabolic syndrome and protects against fatty liver despite increased de novo lipogenesis and dietary conditions known to induce obesity and diabetes.

Fatty-acid biosynthesis and acetyl-coa carboxylase as a target of diclofop, fenoxaprop and other aryloxy-phenoxy-propionic acid herbicides

1988 ◽  
Vol 43 (1-2) ◽  
pp. 47-54 ◽  
Author(s):  
Klaus Kobek ◽  
Manfred Focke ◽  
K. Lichtenthaler Botanisches
Keyword(s):  
Fatty Acid ◽  
Propionic Acid ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Free Acid ◽  
Acetate Incorporation ◽  
Acetyl Coa Carboxylase ◽  
Acid Biosynthesis ◽  
Acetyl Coa ◽  
Acid Herbicides

The effect of the herbicides and aryloxy-phenoxy-propionic acid derivatives diclofop, fenoxaprop, fluazifop and haloxyfop and their ethyl, methyl or butyl esters on the de novo fatty-acid biosynthesis of isolated chloroplasts was investigated with intact chloroplasts isolated from sensitive grasses (Poaceae) and tolerant dicotyledonous plants (Pisum, Spinacia). The 4 herbicides (free-acid form) block the de novo fatty-acid biosynthesis ([2-14C]acetate incorporation into the total fatty-acid fraction) of the sensitive Avena chloroplasts in a dose-dependent manner. The I50- values (a 50% inhibition of the [14C]acetate incorporation) lie in the range of 10-7 to 2 x 10-6 ᴍ. The ethyl or methyl esters (diclofop, fenoxaprop, haloxyfop) and butyl ester (fluazifop) do not affect the de novo fatty-acid biosynthesis of isolated chloroplasts or only at a very high concentration of ca. 10-4 ᴍ. In contrast, the de novo fatty-acid biosynthesis of the tolerant dicotyledonous species (pea, spinach) is not affected by the 4 aryloxy-phenoxy-propionic acid herbicides. In an enzyme preparation isolated from chloroplasts of the herbicide-sensitive barley plants the de novo fatty-acid biosynthesis from [14C]acetate and [14C]acetyl-CoA is blocked by all 4 herbicides (free acids), whereas that of [14C]malonate and [14C]malonyl-CoA is not affected. This strongly suggests that the target of all 4 herbicides (free-acid form) is the acetyl-CoA carboxylase within the chloroplasts. The applied ester derivatives, in turn, which are ineffective in the isolated chloroplast test system, have equally little or no effect on the activity of the acetyl-CoA carboxylase. It is assumed that the acetyl-CoA carboxylase of the tolerant dicot plants investigated is modified in such a way that the 4 herbicides cannot bind to and affect the target

Mislocalization and inhibition of acetyl-CoA carboxylase 1 by a synthetic small molecule

2012 ◽  
Vol 448 (3) ◽  
pp. 409-416 ◽  
Author(s):  
Dongju Jung ◽  
Lutfi Abu-Elheiga ◽  
Rie Ayuzawa ◽  
Ziwei Gu ◽  
Takashi Shirakawa ◽  
...  
Keyword(s):  
Small Molecule ◽  
De Novo ◽  
Selective Inhibition ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Multifunctional Protein ◽  
Malonyl Coa ◽  
Biological Studies ◽  
Synthetic Small Molecule

Chromeceptin is a synthetic small molecule that inhibits insulin-induced adipogenesis of 3T3-L1 cells and impairs the function of IGF2 (insulin-like growth factor 2). The molecular target of this benzochromene derivative is MFP-2 (multifunctional protein 2). The interaction between chromeceptin and MFP-2 activates STAT6 (signal transducer and activator of transcription 6), which subsequently induces IGF inhibitory genes. It was not previously known how the binding of chromeceptin with MFP-2 blocks adipogenesis and activates STAT6. The results of the present study show that the chromeceptin–MFP-2 complex binds to and inhibits ACC1 (acetyl-CoA carboxylase 1), an enzyme important for the de novo synthesis of malonyl-CoA and fatty acids. The formation of this ternary complex removes ACC1 from the cytosol and sequesters it in peroxisomes under the guidance of Pex5p (peroxisomal-targeting signal type 1 receptor). As a result, chromeceptin impairs fatty acid synthesis from acetate where ACC1 is a rate-limiting enzyme. Overexpression of malonyl-CoA decarboxylase or siRNA (small interfering RNA) knockdown of ACC1 results in STAT6 activation, suggesting a role for malonyl-CoA in STAT6 signalling. The molecular mechanism of chromeceptin may provide a new pharmacological approach to selective inhibition of ACC1 for biological studies and pharmaceutical development.

scholarly journals Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation

2021 ◽  
Vol 22 (23) ◽  
pp. 13129
Author(s):  
Marie Octave ◽  
Laurence Pirotton ◽  
Audrey Ginion ◽  
Valentine Robaux ◽  
Sophie Lepropre ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Actin Cytoskeleton ◽  
De Novo ◽  
Lipid Synthesis ◽  
Human Platelets ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Signaling Systems ◽  
Tubulin Acetylation ◽  
The Impact

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton.

scholarly journals Inhibition of acetyl-CoA carboxylase by spirotetramat causes lipid depletion and surface coat deficiency in nematodes

2018 ◽  
Author(s):  
Philipp Gutbrod ◽  
Katharina Gutbrod ◽  
Ralf Nauen ◽  
Abdelnaser Elashry ◽  
Shahid Siddique ◽  
...  
Keyword(s):  
De Novo ◽  
Foliar Application ◽  
Heterodera Schachtii ◽  
Parasitic Nematodes ◽  
Surface Coat ◽  
Acetyl Coa Carboxylase ◽  
Systemic Insecticide ◽  
In Planta ◽  
Acetyl Coa ◽  
Plant Parasitic

AbstractPlant-parasitic nematodes pose a significant threat to agriculture causing annual yield losses worth more than 100 billion US$. Nematode control often involves the use of nematicides, but many of them including non-selective fumigants have been phased out, particularly due to ecotoxicological concerns. Thus new control strategies are urgently needed. Spirotetramat (SPT) is used as phloem-moble systemic insecticide targeting acetyl-CoA carboxylase (ACC) of pest insects and mites upon foliar application. Our studies revealed that SPT known to be activated in planta to SPT-enol acts as a developmental inhibitor of the free-living nematode Caenorhabditis elegans and the plant-parasitic nematode Heterodera schachtii. Exposure to SPT-enol leads to larval arrest and disruption of the life cycle. Furthermore, SPT-enol inhibits nematode ACC activity, affects storage lipids, fatty acid composition and disrupts surface coat synthesis. Silencing of H. schachtii ACC by RNAi induced similar phenotypes and thus mimics the effects of SPT-enol, supporting the conclusion that SPT-enol acts on nematodes by inhibiting ACC. Our studies demonstrated that the inhibition of de novo lipid biosynthesis by interfering with nematode ACC is a new nematicidal mode of action addressed by spirotetramat, a well-known systemic insecticide for sucking pest control.

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