ACETATE AND CHOLESTEROL METABOLISM IN THE HUMAN FOETO-PLACENTAL UNIT AT MIDGESTATION

1970 ◽  
Vol 63 (1) ◽  
pp. 105-118 ◽  
Author(s):  
G. Telegdy ◽  
J. W. Weeks ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Human Placenta ◽  
Sodium Acetate ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Steroid Synthesis ◽  
Homogeneous Form

ABSTRACT Two midgestation placentas were perfused with 2.5 mCi of uniformly labelled 14C-sodium acetate plus 2.5 mCi cholesterol-7α-3H. and two complete foeto-placental units were perfused with 5.0 mCi of 14C-labelled sodium acetate plus 5.0 mCi of cholesterol-7α-3H. The perfusions were carried out at 35–36°C for 90 min. After the perfusion of the isolated placentas, the following 3H-labelled steroids were isolated from the placentas as well as from the perfusates in a radiochemically homogeneous form: pregnenolone (3β-hydroxy-pregn-5-en-20-one), progesterone (pregn-4-ene-3,20-dione), 20α-dihydroprogesterone (20α-hydroxy-pregn-4-en-3-one), 20β-dihydroprogesterone (20β-hydroxy-pregn-4-en-3-one), 17α-hydroxy-pregnenolone (3β,17α-dihydroxy-pregn-5-en-20-one),dehydroepiandrosterone(3β-hydroxy-androst-5-en-17-one) and 17β-oestradiol (oestra-1,3,5(10)-triene-3,17β-diol). The same compounds were also isolated from the placentas following the perfusion of the complete foeto-placental units. With the exception of pregnenolone and progesterone, all steroids were isolated in minute quantities. None of the steroids isolated contained any 14C-label. It is concluded that the midgestation human placenta is not capable of carrying out any de novo steroid synthesis from acetate and that cholesterol is an obligatory precursor in placental steroidogenesis.

ACETATE AND CHOLESTEROL METABOLISM IN THE HUMAN FOETO-PLACENTAL UNIT AT MIDGESTATION

1970 ◽  
Vol 63 (1) ◽  
pp. 119-133 ◽  
Author(s):  
G. Telegdy ◽  
J. W. Weeks ◽  
D. F. Archer ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Sodium Acetate ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Human Foetus ◽  
Homogeneous Form ◽  
Per Se ◽  
Hydroxy Progesterone

ABSTRACT Two complete foeto-placental units were perfused at midgestation with 5.0 mCi of uniformly labelled 14C-sodium acetate plus 5.0 mCi of cholesterol-7α-3H and two isolated foetuses were perfused with 2.5 mCi of 14C-labelled sodium acetate plus 2.5 mCi of cholesterol-7α-3H. The perfusions were carried out at 35–36°C for 90 min. The foetal adrenals, livers, testes and perfusates were analyzed and various labelled steroids were isolated in a radiochemically homogeneous form. Major quantities of 14C- and 3H-labelled pregnenolone (3β-hydroxy-pregn-5-en-20-one) and dehydroepiandrosterone (3β-hydroxy-androst-5-en-17-one) were isolated from the foetal perfusates, livers and adrenals. Minor amounts of 14C- and 3H-labelled progesterone (pregn-4-ene-3,20-dione) were isolated from the perfusates and adrenals, and 17α-hydroxy-progesterone (17α-hydroxy-pregn-4-ene-3,20-dione) and androstenedione (androst-4-ene-3,17-dione) from the perfusates. Smaller amounts of exclusively 14C-labelled androstenedione were isolated also from the adrenals. No labelled progesterone, androstenedione or testosterone (17β-hydroxy-androst-4-en-3-one) was detected in the testes. Attempts to isolate 20α-dihydroprogesterone (20α-hydroxy-pregn-4-en-3-one) or 20β-dihydroprogesterone (20β-hydroxy-pregn-4-en-3-one) from the perfusates, adrenals and livers failed. No labelled cortisol (11β,17,21-trihydroxy-pregn-4-ene-3,20-dione) or corticosterone (11β,21-dihydroxy-pregn-4-ene-3,20-dione) was detected in the adrenals, and no testosterone, oestrone (3-hydroxy-oestra-1,3,5(10)-trien-17-one) or 16α-hydroxy-dehydroepiandrosterone (3β,16α-dihydroxy-androst-5-en-17-one) in the perfusates. Pregnenolone and dehydroepiandrosterone (which were present in approximately equal amounts) accounted for as much as 95% of all steroids isolated from all sources. The bulk of these two steroids was isolated from the perfusates. The 14C/3H ratio of the pregnenolone and dehydroepiandrosterone isolated from the conjugated fraction of the perfusates was much higher than that of the unconjugated compounds. It is concluded that the midgestation human foetus is capable per se of carrying out the de novo synthesis of major quantities of pregnenolone and dehydroepiandrosterone. It is suggested that in foetal steroidogenesis acetate is utilized predominantly via a conjugated pathway and circulating cholesterol mainly via an unconjugated pathway.

ACETATE AND CHOLESTEROL METABOLISM IN THE HUMAN FOETO-PLACENTAL UNIT AT MIDGESTATION.

1970 ◽  
Vol 63 (1) ◽  
pp. 91-104 ◽  
Author(s):  
G. Telegdy ◽  
J. W. Weeks ◽  
U. Lerner ◽  
G. Stakemann ◽  
E. Diczfalusy
Keyword(s):  
Human Placenta ◽  
Metabolic Pathway ◽  
Sodium Acetate ◽  
Cholesterol Metabolism ◽  
The Other ◽  
Human Foetus ◽  
Homogeneous Form ◽  
Other Hand ◽  
Maternal Side

ABSTRACT As the first part of a series of investigations on acetate and cholesterol metabolism, the conversion of acetate to cholesterol was studied in the various compartments of the midgestation foeto-placental unit in perfusion experiments carried out for 90 min at 35–36°C. Following their removal at laparotomy two complete foeto-placental units were perfused each with 5.0 mCi of uniformly labelled sodium acetate-14C + 5.0 mCi of cholesterol-7α-3H. The study was completed by the separate perfusion of two isolated midgestation foetuses and two midgestation placentas. The doses administered in each of these four last experiments were 2.5 mCi of 14C-labelled acetate and 2.5 mCi of 3H-labelled cholesterol. Cholesterol was isolated in a radiochemically homogeneous form from each of the tissues studied. The cholesterol isolated from the placentas, placental perfusates and from the blood bathing the placenta from the maternal side (»maternal perfusates«) contained exclusively 3H-label. On the other hand, the cholesterol isolated from all foetal livers, adrenals, testicles, 3 of 4 residual foetal tissues and 1 out of 4 foetal perfusates also contained significant quantities of 14C-label. It is concluded, that the midgestation human placenta is not capable of synthesizing cholesterol from acetate, but that the conversion of acetate to cholesterol is a quantitatively significant metabolic pathway in the human foetus at midgestation.

QUANTITATIVE ASSESSMENT OF THE DE NOVO STEROL AND STEROID SYNTHESIS IN THE HUMAN FOETO-PLACENTAL UNIT

1971 ◽  
Vol 66 (4) ◽  
pp. 666-678 ◽  
Author(s):  
D. F. Archer ◽  
R. S. Mathur ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Sodium Acetate ◽  
Quantitative Assessment ◽  
De Novo ◽  
Isolation Procedure ◽  
Predominant Formation ◽  
Human Foetus ◽  
Steroid Synthesis ◽  
Internal Standards ◽  
Carbon 14 ◽  
Hydroxy Progesterone

ABSTRACT The quantitative significance of the de novo synthesis of Δ5- and Δ4-steroids was assessed in the midgestation human foetus. Two midgestation foetuses and two complete foeto-placental units were perfused at 36°C for 120 minutes with 3.0 and 6.0 mCi of [14C] sodium acetate, respectively, and radiochemically homogeneous carbon-14 labelled steroids were isolated from the adrenals, livers and perfusates. Losses throughout the isolation procedure were monitored in all tissues of all experiments by the recovery of tritium labelled internal standards. In the four experiments, a total of 18.0 mCi of [14C] sodium acetate was perfused and a total of 0.17 μCi of pregnenolone, 2.65 μCi of pregnenolone sulphate, 1.07 μCi of dehydroepiandrosterone and 8.64 μCi of dehydroepiandrosterone sulphate were isolated. A total of 12.53 μCi were isolated in the form of these four compounds; 10.13 μCi of this was present in the perfusates. In all, 0.07% of the administered [14C]-sodium acetate was converted to the four Δ5-steroids studied and 0.048% to dehydroepiandrosterone sulphate. Progesterone was isolated from the perfusates and liver extracts, and 17α-hydroxy-progesterone, androstenedione and testosterone from the perfusates. In the four experiments, a total of 0.045 μCi of carbon-14 labelled Δ4-steroids were isolated, predominantly from the perfusates. In all, less than 0.0003% of the perfused [14C] sodium acetate was converted to Δ4-steroids. Thus, almost 300 times more Δ5- than Δ4-steroids were formed. It is concluded that the extensive de novo steroidogenetic processes taking place in the midgestation human foetus lead to the predominant formation of Δ5-steroid sulphates.

QUANTITATIVE ASSESSMENT OF THE DE NOVO STEROL AND STEROID SYNTHESIS IN THE HUMAN FOETO-PLACENTAL UNIT.

1970 ◽  
Vol 65 (4) ◽  
pp. 663-674 ◽  
Author(s):  
R. S. Mathur ◽  
D. F. Archer ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Sodium Acetate ◽  
Quantitative Assessment ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Internal Standard ◽  
The Other ◽  
Radioactive Material ◽  
Human Foetus ◽  
Steroid Synthesis ◽  
Average Quantity

ABSTRACT In order to assess the quantitative significance of the de novo cholesterol synthesis in the foeto-placental unit at midgestation, two midgestation foetuses and two complete foeto-placental units were perfused with [14C]-sodium acetate immediately following their removal at laparotomy. The perfusions were carried out at 36°C for 120 min administering 3.0 and 6.0 mCi of [14C] sodium acetate, respectively. The amount of [14C]-cholesterol formed was estimated on the basis of the recovery of [7α-3H]-cholesterol internal standard present in the radiochemically homogeneous cholesterol isolated from the various tissues. The cholesterol isolated from the placentas was devoid of any [14C] label. On the other hand, [14C] cholesterol was isolated from all perfusates, as well as from all foetal tissues studied, including the adrenals, livers, testicles, brains and residual foetal tissues. The average quantity of radiochemically homogeneous [14C] cholesterol formed by the four foetuses corresponded to 0.68% of the radioactive material perfused: 0.45% was isolated from the liver, 0.13% from the adrenals, 0.01% from the testicles and 0.08% from the perfusates. Cholesterol sulphate was also isolated from the extracts of adrenals, livers and perfusates. The quantity of [14C] cholesterol sulphate formed was much less than that of [14C] cholesterol; following correction for procedural losses, the total amount of [14C] cholesterol sulphate isolated did not exceed 0.01% of the perfused material. It is concluded that the midgestation human foetus synthesizes large quantities of cholesterol, utilizing small molecular material such as sodium acetate as a precursor and that part of the cholesterol synthesized by the foetus is secreted to the placenta.

scholarly journals Revisiting Steroidogenic Pathways in the Human Placenta and Primary Human Trophoblast Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 1704
Author(s):  
Rona Karahoda ◽  
Sampada Kallol ◽  
Michael Groessl ◽  
Edgar Ontsouka ◽  
Pascale Anderle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gestational Age ◽  
Human Placenta ◽  
De Novo ◽  
Expression Patterns ◽  
Pcr Analysis ◽  
Trophoblast Cells ◽  
Steroidogenic Enzymes ◽  
Steroid Synthesis ◽  
Human Trophoblast

Steroid hormones play a crucial role in supporting a successful pregnancy and ensuring proper fetal development. The placenta is one of the principal tissues in steroid production and metabolism, expressing a vast range of steroidogenic enzymes. Nevertheless, a comprehensive characterization of steroidogenic pathways in the human placenta and potential developmental changes occurring during gestation are poorly understood. Furthermore, the specific contribution of trophoblast cells in steroid release is largely unknown. Thus, this study aimed to (i) identify gestational age-dependent changes in the gene expression of key steroidogenic enzymes and (ii) explore the role of trophoblast cells in steroid biosynthesis and metabolism. Quantitative and Droplet Digital PCR analysis of 12 selected enzymes was carried out in the first trimester (n = 13) and term (n = 20) human placentas. Primary trophoblast cells (n = 5) isolated from human term placentas and choriocarcinoma-derived cell lines (BeWo, BeWo b30 clone, and JEG-3) were further screened for gene expression of enzymes involved in placental synthesis/metabolism of steroids. Finally, de novo steroid synthesis by primary human trophoblasts was evaluated, highlighting the functional activity of steroidogenic enzymes in these cells. Collectively, we provide insights into the expression patterns of steroidogenic enzymes as a function of gestational age and delineate the cellular origin of steroidogenesis in the human placenta.

scholarly journals Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009891
Author(s):  
Baocai Xie ◽  
Xiaochen Shi ◽  
Yan Li ◽  
Bo Xia ◽  
Jia Zhou ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherogenic Diet ◽  
Standard Diet ◽  
Low Levels ◽  
Reduced Risk

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.

Genetic defects in sterol synthesis, absorption, and degradation into bile acids

2011 ◽  
pp. 1673-1676
Author(s):  
Stefano Romeo
Keyword(s):  
Membrane Permeability ◽  
Bile Acids ◽  
Steroid Hormones ◽  
Cell Membranes ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
The Body ◽  
Sterol Synthesis ◽  
Genetic Defects ◽  
And Function

Cholesterol is the most abundant steroid in animals. Not only is it a vital constituent of cell membranes, where it establishes proper membrane permeability and fluidity, but it is also the immediate metabolic precursor of all known steroid hormones and bile acids. Synthesized de novo in cells or absorbed from the diet, cholesterol circulates in the body in association with lipoproteins and is ultimately degraded into bile acids by the liver. Every perturbation of the numerous enzymes involved in cholesterol metabolism leads to impairment in the development and function of the gastrointestinal, cardiovascular, skeletal, and nervous systems.

scholarly journals Coxiella burnetii Expresses a Functional Δ24 Sterol Reductase

2010 ◽  
Vol 192 (23) ◽  
pp. 6154-6159 ◽  
Author(s):  
Stacey D. Gilk ◽  
Paul A. Beare ◽  
Robert A. Heinzen
Keyword(s):  
Host Cell ◽  
Coxiella Burnetii ◽  
Fluorescent Protein ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Q Fever ◽  
Parasitophorous Vacuole ◽  
Cholesterol Biosynthesis ◽  
Brefeldin A ◽  
Ergosterol Biosynthesis

ABSTRACT Coxiella burnetii, the etiological agent of human Q fever, occupies a unique niche inside the host cell, where it replicates in a modified acidic phagolysosome or parasitophorous vacuole (PV). The PV membrane is cholesterol-rich, and inhibition of host cholesterol metabolism negatively impacts PV biogenesis and pathogen replication. The precise source(s) of PV membrane cholesterol is unknown, as is whether the bacterium actively diverts and/or modifies host cell cholesterol or sterol precursors. C. burnetii lacks enzymes for de novo cholesterol biosynthesis; however, the organism encodes a eukaryote-like Δ24 sterol reductase homolog, CBU1206. Absent in other prokaryotes, this enzyme is predicted to reduce sterol double bonds at carbon 24 in the final step of cholesterol or ergosterol biosynthesis. In the present study, we examined the functional activity of CBU1206. Amino acid alignments revealed the greatest sequence identity (51.7%) with a Δ24 sterol reductase from the soil amoeba Naegleria gruberi. CBU1206 activity was examined by expressing the protein in a Saccharomyces cerevisiae erg4 mutant under the control of a galactose-inducible promoter. Erg4 is a yeast Δ24 sterol reductase responsible for the final reduction step in ergosterol synthesis. Like Erg4-green fluorescent protein (GFP), a CBU1206-GFP fusion protein localized to the yeast endoplasmic reticulum. Heterologous expression of CBU1206 rescued S. cerevisiae erg4 sensitivity to growth in the presence of brefeldin A and cycloheximide and resulted in new synthesis of ergosterol. These data indicate CBU1206 is an active sterol reductase and suggest the enzyme may act on host sterols during C. burnetii intracellular growth.

EFFECT OF HYPOPHYSECTOMY ON CHOLESTEROL METABOLISM IN THE TESTES OF RATS AND MICE

1972 ◽  
Vol 52 (2) ◽  
pp. 321-326 ◽  
Author(s):  
A. A. HAFIEZ ◽  
A. BARTKE
Keyword(s):  
Total Cholesterol ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Cholesterol Content ◽  
Testicular Tissue ◽  
Testis Weight ◽  
Acetate Incorporation ◽  
Rats And Mice

SUMMARY Increased synthesis de novo of cholesterol by testes of rats and mice was found to be a contributing factor in the increased testicular cholesterol content after hypophysectomy. This was shown by increased [1-14C]acetate incorporation in vitro into free and esterified cholesterol by testicular tissue from rats and mice hypophysectomized 3 weeks earlier, as compared with intact controls. In mice, testicular cholesterol content was significantly increased 1 day after hypophysectomy at which time there was no change in the testis weight. Three weeks after the operation there was a significant decrease in testis weight and a significant increase in the concentration of free, esterified and total cholesterol as well as in the percentage of esterified fraction. These changes were even more pronounced 1 month later.

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