Pharmacological AMP-kinase activators have compartment-specific effects on cell physiology

2011 ◽  
Vol 301 (6) ◽  
pp. C1307-C1315 ◽  
Author(s):  
Mohamed Kodiha ◽  
Dennis Ho-Wo-Cheong ◽  
Ursula Stochaj
Keyword(s):  
De Novo ◽  
Cell Physiology ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Α Subunit ◽  
Physiological Processes ◽  
Specific Effects ◽  
The Impact ◽  
Nuclear Processes

5′-AMP-activated kinase (AMPK) regulates numerous biological events and is an essential target for the treatment of type 2 diabetes. The objectives of the present study were first to determine the compartment-specific effects of three established AMPK activators on Thr172 phosphorylation of the α-subunit, an indicator of AMPK activation. Second, we examined how cytoplasmic and nuclear processes are modulated by pharmacological AMPK activators. Specifically, the impact of phenformin, resveratrol, and 5-aminoimidazole-4-carboxamide riboside (AICAR) on Thr172 phosphorylation in the cytoplasm and nucleus was quantified by different methods. To analyze how these activators change cell physiology, we measured the inactivation of acetyl-CoA-carboxylase 1, a predominantly cytoplasmic enzyme that is crucial for lipid metabolism. As a criterion for activities associated with the nucleus, de novo RNA synthesis in nucleoli was quantified. Our studies demonstrate that pharmacological activators of AMPK can alter the balance between nuclear and cytoplasmic AMPK pools. Thus, phenformin and resveratrol caused a strong activation of AMPK in the cytoplasm, whereas the effect was less pronounced in nuclei. By contrast, AICAR elicited a comparable rise in Thr172 phosphorylation in both compartments. Notably, these activators differed drastically in their effects on physiological processes that are located in distinct subcellular compartments. All compounds led to a substantial inactivation of acetyl-CoA-carboxylase 1 in the cytoplasm, with only minor changes to the nuclear enzyme. In the nucleolus, transcription was strongly inhibited by resveratrol, while a moderate inhibition was observed with phenformin and AICAR. Taken together, the compartment-specific phosphorylation of AMPK and downstream events are determined by the activator.

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.

Insulin receptor and cancer

2011 ◽  
Vol 18 (4) ◽  
pp. R125-R147 ◽  
Author(s):  
Antonino Belfiore ◽  
Roberta Malaguarnera
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Cancer Progression ◽  
De Novo ◽  
Promoting Effect ◽  
Autocrine Loop ◽  
Stem Cell Expansion ◽  
Increased Sensitivity ◽  
The Impact

The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies.De novoactivation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.

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.

scholarly journals THE IMPACT OF ESSENTIAL OILS OF THE LAMIACEAE FAMILY AGAINST TYLENCHULUS SEMIPENETRANS USING MOLECULAR MODELING METHODS

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bekkal Brikci S. ◽  
Abdelli I. ◽  
Hassani F. ◽  
Bereksi Reguig M.
Keyword(s):  
Essential Oils ◽  
Control Method ◽  
Acid Synthesis ◽  
Dynamics Simulation ◽  
Acetyl Coa Carboxylase ◽  
Chemical Insecticide ◽  
Ligand Complex ◽  
Acetyl Coa ◽  
Tylenchulus Semipenetrans ◽  
The Impact

Tylenchulus semipenetrans is an economically important plant-parasitic nematode occurring in all citrus-producing regions of the world and causing a disease called “slow decline”. Chemical nematicides commonly used in agriculture have ecotoxicological effects. As a control method, attention has been paid to bio-nematicides that do not exhibit harmful effects on the ecosystem. In this study we will carry out the in scilico experiments in order to find the most coherent Enzyme-Ligand complex to lead to the best inhibitors of Acetyl CoA Carboxylase in Citrus Tylenchulus semipenetrans nematode. “Acetyl CoA Carboxylase” enzyme responsible for fatty acid synthesis in Tylenchulus semipenetrans, its alteration disrupting the synthesis of the surface layer, this inhibitory action is based on essential oils of aromatic plants, taking as an example the Lamiaceae family, using natural compounds extract from essential oils of Salvia verbenaca, Lavandula stoechas, Rosmarinus officinalis, and Thymus ciliatus. This study revealed for the first time that ?-phellandrène from Salvia verbenaca gives the best docking scores compared to Biotine, the co-crystallized inhibitor of the Acetyl CoA Carboxylase, to spirotetramat as chemical insecticide already used against citrus nematode, and to the other complexes. After that, the Molecular Dynamics Simulation study showed a good result for the ?-phellandrène- Acetyl CoA Carboxylase docked complex, for that we can consider that ?-phellandrène extracted from Salvia verbenaca’s essential oil as a functional inhibitor of Acetyl CoA Carboxylase activities and it can be used as good bio-nematicides against Tylenchulus semipenetrans.

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.

Sign in / Sign up

Export Citation Format

Share Document