scholarly journals Studies on the mechanism and regulation of C-4 demethylation in cholesterol biosynthesis. The role of adenosine 3′:5′-cyclic monophosphate

1971 ◽  
Vol 125 (2) ◽  
pp. 625-634 ◽  
Author(s):  
D. P. Bloxham ◽  
D. C. Wilton ◽  
M. Akhtar
Keyword(s):  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Microsomal Preparation ◽  
Aerobic Conditions ◽  
Dehydrogenase Enzyme ◽  
Labelled Compound ◽  
Nad 4 ◽  
Liver Microsomal Preparation ◽  
Compound Ii

1. An assay for demethylation has been developed based on the release of tritium from 4,4-dimethyl[3α-3H]cholest-7-en-3β-ol (II). 2. The maximum release of 3H from 3α-3H-labelled compound (II) in a rat liver microsomal preparation occurs in the presence of NADPH and NAD+ under aerobic conditions. 3. Incubation of 3α-3H-labelled compound (II) with NADPH under aerobic conditions leads to the formation of a 3α-3H-labelled C-4 carboxylic acid. This compound undergoes dehydrogenation on subsequent anaerobic incubation with NAD+. 4. The 3H released from the steroid was located in [4-3H]nicotinamide and the medium. Incubation with synthetic [4-3H2]NADH gave a similar result. 5. In the presence of glutamate dehydrogenase and α-oxoglutarate part of the 3H released from the steroid was transferred to glutamate. 6. A series of 3-oxo steroids were reduced equally well by [4-3H2]NADH and [4-3H2]NADPH. The reduction of 5α-cholest-7-en-3-one was shown to use the 4B H atom from the nucleotide. 7. 3′:5′-Cyclic AMP was shown to be a competitive inhibitor of the 3β-hydroxy dehydrogenase enzyme in the demethylation reaction.

scholarly journals 4,4′-dimethylcholesta-7,9,14-trienol is an intermediate in the demethylation of dihydroagnosterol

1977 ◽  
Vol 166 (1) ◽  
pp. 17-20 ◽  
Author(s):  
I A F Tavares ◽  
K A Munday ◽  
D C Wilton
Keyword(s):  
Rat Liver ◽  
Liver Homogenate ◽  
Anaerobic Conditions ◽  
Microsomal Preparation ◽  
Aerobic Conditions ◽  
Liver Microsomal Preparation

1. 4,4′-Dimethylcholesta-7,9,14-trienol is an intermediate in the metabolism of dihydroagnosterol to cholesterol by rat liver homogenate. 2. This triene is reduced by a rat liver microsomal preparation in the presence of NADPH to give 4,4′-dimethylcholesta-7,9-dienol under anaerobic conditions. 3. Reduction of the triene in the presence of [4-3H2]NADPH resulted in the incorporation of 3H into the product. 4. Under aerobic conditions the triene is converted into cholesterol by a rat liver homogenate.

The role of secondary alcoholic groups of D-galacturonan in its degradation with exo-D-galacturonanase

1980 ◽  
Vol 45 (2) ◽  
pp. 427-434 ◽  
Author(s):  
Kveta Heinrichová ◽  
Rudolf Kohn
Keyword(s):  
Acetyl Derivative ◽  
Competitive Inhibitor ◽  
Hydroxyl Groups ◽  
Pectic Acid ◽  
Substrate Complex ◽  
Enzyme Substrate ◽  
The Individual ◽  
Degradation Degree ◽  
Derivatives Of

The effect of exo-D-galacturonanase from carrot on O-acetyl derivatives of pectic acid of variousacetylation degree was studied. Substitution of hydroxyl groups at C(2) and C(3) of D-galactopyranuronic acid units influences the initial rate of degradation, degree of degradation and its maximum rate, the differences being found also in the time of limit degradations of the individual O-acetyl derivatives. Value of the apparent Michaelis constant increases with increase of substitution and value of Vmax changes. O-Acetyl derivatives act as a competitive inhibitor of degradation of D-galacturonan. The extent of the inhibition effect depends on the degree of substitution. The only product of enzymic reaction is D-galactopyranuronic acid, what indicates that no degradation of the terminal substituted unit of O-acetyl derivative of pectic acid takes place. Substitution of hydroxyl groups influences the affinity of the enzyme towards the modified substrate. The results let us presume that hydroxyl groups at C(2) and C(3) of galacturonic unit of pectic acid are essential for formation of the enzyme-substrate complex.

scholarly journals Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Peter Dornbos ◽  
Amanda Jurgelewicz ◽  
Kelly A. Fader ◽  
Kurt Williams ◽  
Timothy R. Zacharewski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Cholesterol Homeostasis ◽  
Hepatic Glycogen ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Aryl Hydrocarbon ◽  
The Impact

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

scholarly journals Hydrogen Peroxide Toxicity Induces Ras Signaling in Human Neuroblastoma SH-SY5Y Cultured Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Jirapa Chetsawang ◽  
Piyarat Govitrapong ◽  
Banthit Chetsawang
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Viability ◽  
Cultured Cells ◽  
Neuronal Cells ◽  
Competitive Inhibitor ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Human Neuroblastoma ◽  
Dependent Signaling Pathway

It has been reported that overproduction of reactive oxygen species occurs after brain injury and mediates neuronal cells degeneration. In the present study, we examined the role of Ras signaling on hydrogen peroxide-induced neuronal cells degeneration in dopaminergic neuroblastoma SH-SY5Y cells. Hydrogen peroxide significantly reduced cell viability in SH-SY5Y cultured cells. An inhibitor of the enzyme that catalyzes the farnesylation of Ras proteins, FTI-277, and a competitive inhibitor of GTP-binding proteins, GDP-beta-S significantly decreased hydrogen peroxide-induced reduction in cell viability in SH-SY5Y cultured cells. The results of this study might indicate that a Ras-dependent signaling pathway plays a role in hydrogen peroxide-induced toxicity in neuronal cells.

Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function

1991 ◽  
Vol 261 (2) ◽  
pp. R323-R328 ◽  
Author(s):  
M. A. Perrella ◽  
F. L. Hildebrand ◽  
K. B. Margulies ◽  
J. C. Burnett
Keyword(s):  
Renal Function ◽  
Competitive Inhibitor ◽  
Vehicle Group ◽  
Relaxing Factor ◽  
Anesthetized Dogs ◽  
Endothelium Derived Relaxing Factor ◽  
Renal Vascular ◽  
Renal Responses

The endothelium has emerged as an important modulator of vascular tone by producing both vasodilating and vasoconstricting substances. In vitro studies have demonstrated that endothelial cells produce endothelium-derived relaxing factor (EDRF), which promotes vasodilation via the stimulation of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). However, the role of EDRF in the basal regulation of cardiopulmonary and renal function is not well defined. The present study was therefore designed to assess the function of EDRF by studying two groups of normal anesthetized dogs, of which one received a competitive inhibitor to EDRF generation, NG-monomethyl-L-arginine (L-NMMA; 50 micrograms.kg-1.min-1 iv), and the other received a vehicle. The L-NMMA infusion produced no significant increase in mean arterial pressure but marked increases in systemic, pulmonary, and renal vascular resistances compared with the vehicle group. Although renal blood flow decreased with L-NMMA, no changes were observed in glomerular filtration rate or sodium excretion. Associated with the cardiopulmonary and renal responses with L-NMMA was a modest increase in plasma endothelin (7.9 +/- 1.3 to 10.2 +/- 1.8 pg/ml, P less than 0.05), an endothelium-derived vasoconstrictor. No alteration was observed in plasma or urinary cGMP with EDRF inhibition. These cardiopulmonary and renal responses with L-NMMA may be attributed not only to EDRF inhibition but to an imbalance between endothelium-derived relaxing and contracting factors.

scholarly journals Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rachna Manek ◽  
Yao V. Zhang ◽  
Patricia Berthelette ◽  
Mahmud Hossain ◽  
Cathleen S. Cornell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Animal Behavior ◽  
Phenylalanine Hydroxylase ◽  
Cholesterol Biosynthesis ◽  
Blood Phenylalanine ◽  
Liver Functions ◽  
Unknown Lipid ◽  
Pah Gene

AbstractPhenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.

Herbicide-Induced Ethylene Production: Role of the Gas in Sublethal Doses of 2,4-D

Weed Science ◽  
1968 ◽  
Vol 16 (4) ◽  
pp. 498-500 ◽  
Author(s):  
F. B. Abeles
Keyword(s):  
Carbon Dioxide ◽  
Zea Mays ◽  
Glycine Max ◽  
Ethylene Production ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Dichlorophenoxyacetic Acid ◽  
Sublethal Doses ◽  
2,4 Dichlorophenoxyacetic Acid

Ethylene production was stimulated by 2,4-dichlorophenoxyacetic acid (2,4-D) from light-grown corn (Zea mays L., var. XL-15) and soybeans (Glycine max Merr., var. Hawkeye). Ethylene had an inhibitory effect on the growth of corn and soybeans, but a reversal of the ethylene effect could not be clearly demonstrated using the competitive inhibitor, carbon dioxide. Ethylene did not mimic the ability of 2,4-D to cause growth curvatures. It was concluded that ethylene played a role in the activity of sublethal amounts of 2,4-D.

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