Mechanisms of cholesterol synthesis inhibition by D-glucosamine

1985 ◽  
Vol 63 (12) ◽  
pp. 1253-1257 ◽  
Author(s):  
Susan J. Friedman ◽  
Stanley Cheng ◽  
Philip Skehan
Keyword(s):  
Cholesterol Biosynthesis ◽  
Lipid Synthesis ◽  
Amino Sugar ◽  
Sterol Synthesis ◽  
Cholesteryl Esters ◽  
Acetate Incorporation ◽  
Glial Tumor ◽  
Acetyl Coa ◽  
Wide Range ◽  
Acetate Utilization

The amino sugar D-glucosamine possesses antitumor activity which is thought to depend in part upon its ability to impair cholesterol biosynthesis and damage cellular membranes. The present study examined the effect of glucosamine on acetate utilization for lipid and sterol synthesis in rat C6 glial tumor cells. At cytotoxic concentrations, the amino sugar inhibited [14C]acetate incorporation into nonesterified sterols and lipids but increased the flow of label into cholesteryl esters. A comparison of the rates of acetate utilization for glucosamine metabolism (N-acetylation) and sterol and lipid synthesis suggested that glucosamine might act by competing for a common cytosolic pool of acetyl CoA. The inhibition of lipid and sterol synthesis, however, remained constant over a wide range of extracellular acetate concentrations. These results suggest that, if glucosamine acts by restricting the supply of acetate for these biosynthetic processes, it probably inhibits a step prior to the formation of acetyl CoA. Alternative mechanisms are discussed.

scholarly journals Acetylation-mediated phase control of the nucleolus regulates cellular acetyl-CoA responses

2020 ◽  
Author(s):  
Ryan Houston ◽  
Shiori Sekine ◽  
Michael J. Calderon ◽  
Fayaz Seifuddin ◽  
Guanghui Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Culture Media ◽  
Lipid Synthesis ◽  
Essential Element ◽  
Cell System ◽  
Cellular Functions ◽  
Acetyl Coa ◽  
Atp Production ◽  
Wide Range ◽  
A Cell

SummaryThe metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using CRISPR-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa HDAC deacetylases regulating the phase state of the nucleolus. Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

scholarly journals Lipid biosynthesis in liver slices of the foetal guinea pig

1976 ◽  
Vol 154 (1) ◽  
pp. 149-158 ◽  
Author(s):  
C T Jones ◽  
I K Ashton
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Fatty Acid Synthetase ◽  
Lipid Synthesis ◽  
Short Chain Fatty Acids ◽  
Acetate Incorporation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Citrate Lyase ◽  
Effect Of Glucose

Lipid synthesis as measured by the incorporation of acetate or 3H2O into slices of foetal liver, is much higher than in slices of adult liver and shows a peak at about two-thirds of gestation. At this time the synthesis from glucose was low and reached a peak 10 days later. The changes in the activity of ATP citrate lyase, which mirrored acetate incorporation, and the effect of glucose and pyruvate on acetate corporation into lipid suggests that some of the lipid synthesis occurs via intramitochondrial acetyl-CoA production from acetate. Despite this, lipid synthesis was not inhibited by (-)-hydroxycitrate. The low rate of synthesis from glucose at two-thirds of gestation is ascribed to the low activity of pyruvate carboxylase at this time and a role for a phosphoenolpyruvate carboxykinase in providing oxaloacetate for lipogenesis is proposed. The activity of fatty acid synthetase broadly agreed with the changes in lipid synthesis, whereas the activity of acetyl-CoA carboxylase was barely sufficient to account for the rates of lipid synthesis in vivo. Acetate and short-chain fatty acids are likely to be the major precursors for lipid synthesis in vivo.

scholarly journals Acetyl-CoA carboxylase inhibition alters tubulin acetylation and aggregation in thrombin-stimulated platelets

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
M Octave ◽  
L Pirotton ◽  
A Ginion ◽  
V Robaux ◽  
S Lepropre ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Lipid Content ◽  
Thrombus Formation ◽  
Lipid Synthesis ◽  
Phospholipid Content ◽  
Acetate Incorporation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Tubulin Acetylation ◽  
Platelet Functions

Abstract Introduction Acetyl-CoA carboxylase (ACC), the first enzyme regulating lipid synthesis, promotes thrombus formation by increasing platelet phospholipid content. Inhibition of its activity decreases lipogenesis and increases the content in acetyl-CoA which can serve as a substrate for protein acetylation. This posttranslational modification plays a key role in the regulation of platelet aggregation, via tubulin acetylation. Purpose To demonstrate that ACC inhibition may affect platelet functions via an alteration of lipid content and/or tubulin acetylation. Methods Platelets were treated 2 hours with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. Platelet functions were assessed by aggregometry and flow cytometry. Lipogenesis was measured via 14C-acetate incorporation into lipids. Lipidomics analysis was carried out on the commercial Lipidyzer platform. Protein phosphorylation and acetylation were evaluated by western blot. Results Treatment with CP640.186 drastically decreased platelet lipogenesis. However, the quantitative lipidomics analyses showed that preincubation with the compound did not affect global platelet lipid content. Interestingly, this short-term ACC inhibition was sufficient to increase tubulin acetylation level, at basal state and after thrombin stimulation. It was associated with an impaired platelet aggregation, in response to low thrombin concentration, while granules secretion was not affected. Mechanistically, we highlighted a decrease in Rac1 activity, associated with a reduced phosphorylation of its downstream effector PAK2. Surprisingly, actin cytoskeleton was not impacted but we evidenced a significant decrease in ROS production which could result from a decreased NOX2 activity. Conclusion Pharmacological ACC inhibition decreases platelet aggregation upon thrombin stimulation. The mechanism depends on increased tubulin acetylation, with subsequent alteration of the Rac1/PAK2/NOX2 signaling pathway FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Fonds pour la formation à la Recherche dans l'Industrie et l'Agriculture (FRIA)

scholarly journals Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000981
Author(s):  
Ryan Houston ◽  
Shiori Sekine ◽  
Michael J. Calderon ◽  
Fayaz Seifuddin ◽  
Guanghui Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Histone Deacetylases ◽  
Culture Media ◽  
Lipid Synthesis ◽  
Essential Element ◽  
Cell System ◽  
Acetyl Coa ◽  
Atp Production ◽  
Wide Range ◽  
A Cell

The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

Inhibition kinetics for propionate degradation using propionate-enriched mixed cultures

1998 ◽  
Vol 38 (8-9) ◽  
pp. 443-451 ◽  
Author(s):  
S. H. Hyun ◽  
J. C. Young ◽  
I. S. Kim
Keyword(s):  
Phase I ◽  
Competitive Inhibition ◽  
Gas Production ◽  
Phase Iii ◽  
Utilization Rate ◽  
Inhibition Kinetics ◽  
Wide Range ◽  
Propionate Degradation ◽  
Acetate Utilization ◽  
Velocity Coefficient

To study propionate inhibition kinetics, seed cultures for the experiment were obtained from a propionate-enriched steady-state anaerobic Master Culture Reactor (MCR) operated under a semi-continuous mode for over six months. The MCR received a loading of 1.0 g propionate COD/l-day and was maintained at a temperature of 35±1°C. Tests using serum bottle reactors consisted of four phases. Phase I tests were conducted for measurement of anaerobic gas production as a screening step for a wide range of propionate concentrations. Phase II was a repeat of phase I but with more frequent sampling and detailed analysis of components in the liquid sample using gas chromatography. In phase III, different concentrations of acetate were added along with 1.0 g propionate COD/l to observe acetate inhibition of propionate degradation. Finally in phase IV, different concentrations of propionate were added along with 100 and 200 mg acetate/l to confirm the effect of mutual inhibition. Biokinetic and inhibition coefficients were obtained using models of Monod, Haldane, and Han and Levenspiel through the use of non-linear curve fitting technique. Results showed that the values of kp, maximum propionate utilization rate, and Ksp, half-velocity coefficient for propionate conversion, were 0.257 mg HPr/mg VSS-hr and 200 mg HPr/l, respectively. The values of kA, maximum acetate utilization rate, and KsA, half-velocity coefficient for acetate conversion, were 0.216 mg HAc/mg VSS-hr and 58 mg HAc/l, respectively. The results of phase III and IV tests indicated there was non-competitive inhibition when the acetate concentration in the reactor exceeded 200 mg/l.

AN INCREASED RATE OF CHOLESTEROL BIOSYNTHESIS WITH MICROSOME FRACTIONS OF LIVER FROM KETOTIC GUINEA PIGS

1962 ◽  
Vol 40 (1) ◽  
pp. 1749-1762 ◽  
Author(s):  
F. Sauer
Keyword(s):  
Young Adult ◽  
Guinea Pigs ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Maximum Activity ◽  
Sterol Synthesis ◽  
Differential Centrifugation ◽  
Microsome Fraction ◽  
Liver Homogenates ◽  
Increased Activity

Cholesterol synthesis was studied in liver fractions obtained by differential centrifugation from young, adult, and ketotic guinea pigs. Both 10,000 × g and 105,000 × g sediment was required for maximum activity. Incubations were carried out in the presence of appropriate liver fractions from young guinea pigs in order to overcome the low rates of cholesterol synthesis in liver homogenates from adult guinea pigs. Microsome fractions from ketotic hyperlipemic guinea pigs actively promoted sterol synthesis when incubated with mitochondria plus supernatant from young guinea pigs, while microsome fractions from adult controls (fed or starved) decreased the rate of sterol synthesis in the same incubation system. The results of this investigation indicate that microsomes from hyperlipemic ketotic guinea pigs do not have a block in cholesterol synthesis characteristic of microsomes from starved animals, and that this microsome fraction has increased activity of HMG-CoA2reductase, one of the key enzymes of cholesterol synthesis.

scholarly journals Modulation of lipid-synthesizing enzymes by insulin in differentiated ob17 adipose-like cells

1983 ◽  
Vol 214 (2) ◽  
pp. 443-449 ◽  
Author(s):  
P Grimaldi ◽  
C Forest ◽  
P Poli ◽  
R Negrel ◽  
G Ailhaud
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Specific Activity ◽  
Fatty Acid Synthetase ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acetate Incorporation ◽  
Long Term Effects ◽  
Response Curves ◽  
Glycerol 3 Phosphate Dehydrogenase

ob17 cells convert into adipose-like cells when maintained in the presence of physiological concentrations of insulin and tri-iodothyronine. After this conversion, insulin removal from differentiated ob17 cells gives within 24-48 h a large decrease in fatty acid synthetase, glycerol 3-phosphate dehydrogenase and acid:CoA ligase activities, as well as in the rate of fatty acid synthesis determined by [14C]acetate incorporation into lipids. All parameters are restored by insulin addition to initial values within 24-48 h. Dose-response curves of insulin on the restoration of glycerol 3-phosphate dehydrogenase activity and of fatty acid synthesis give half-maximally effective concentrations close to 1 nM, in agreement with the affinity for insulin of the insulin receptors previously characterized in these cells. Immunotitration experiments indicate that the changes in the specific activity of fatty acid synthetase are due to parallel changes in the cellular enzyme content. Therefore the ob17 cell line should be a useful model to study the long-term effects of insulin on the modulation of lipid synthesis in adipose cells.

scholarly journals Nef Induces Multiple Genes Involved in Cholesterol Synthesis and Uptake in Human Immunodeficiency Virus Type 1-Infected T Cells

2005 ◽  
Vol 79 (15) ◽  
pp. 10053-10058 ◽  
Author(s):  
Angélique B. van ′t Wout ◽  
J. Victor Swain ◽  
Michael Schindler ◽  
Ushnal Rao ◽  
Melissa S. Pathmajeyan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Acetate Incorporation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Several recent reports indicate that cholesterol might play an important role in human immunodeficiency virus type 1 (HIV-1) replication. We investigated the effects of HIV-1 infection on cholesterol biosynthesis and uptake using microarrays. HIV-1 increased gene expression of cholesterol genes in both transformed T-cell lines and primary CD4+ T cells. Consistent with our microarray data, 14C-labeled mevalonate and acetate incorporation was increased in HIV-1-infected cells. Our data also demonstrate that changes in cholesterol biosynthesis and uptake are only observed in the presence of functional Nef, suggesting that increased cholesterol synthesis may contribute to Nef-mediated enhancement of virion infectivity and viral replication.

Inhibitors of sterol synthesis. Concerning the structure of 15β-methyl-5α,14β-cholest-7-ene-3β,15α-diol, an inhibitor of cholesterol biosynthesis

1988 ◽  
Vol 46 (4) ◽  
pp. 245-251 ◽  
Author(s):  
Samuel T. Bowen ◽  
Edward J. Parish ◽  
William K. Wilson ◽  
George J. Schroepfer ◽  
Florante A. Quiocho
Keyword(s):  
Cholesterol Biosynthesis ◽  
Sterol Synthesis
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