Hepatic and intestinal formation of polar sterols in vivo in animals fed on a cholesterol-supplemented diet

In rats fed on a diet containing 1% cholesterol for 24 h, the decrease in hepatic non-saponifiable lipid synthesis, cholesterogenesis and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was accompanied by an increase in the proportion of newly synthesized polar sterols in vivo. In these animals there was also a strong inverse correlation between the proportion of polar sterols in the non-saponifiable lipid and hepatic HMG-CoA reductase activity. A similar correlation was not observed in animals fed on a normal diet. Cholesterogenesis in the intestine was not as sensitive to inhibition by dietary cholesterol as was that in the liver, and there was no increase in the polar-sterol content of the newly synthesized non-saponifiable-lipid fraction.

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Role of reversible phosphorylation in mediating changes in the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase during pregnancy and lactation in the rat

Biochemical Journal ◽

10.1042/bj2480993 ◽

1987 ◽

Vol 248 (3) ◽

pp. 993-996 ◽

Cited By ~ 1

Author(s):

R A Easom ◽

V A Zammit

Keyword(s):

Reductase Activity ◽

Post Partum ◽

Active Form ◽

Total Activity ◽

Female Rats ◽

Hmg Coa Reductase ◽

Pregnancy And Lactation ◽

Coa Reductase

1. The expressed and total (completely dephosphorylated) activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase were measured in microsomal fractions isolated from cold-clamped liver samples from female rats in various stages of the reproductive cycle. 2. There was little change in total HMG-CoA reductase activity during pregnancy and early lactation, but after 2 days post partum there was a marked increase in total activity. 3. The expressed/total activity ratio of HMG-CoA reductase showed a profound decrease during the last 2 days of pregnancy. The fraction of the enzyme in the active form increased progressively during the first 2 days of lactation. 4. The combined effect of these changes was that the expressed activity of HMG-CoA reductase changed in parallel with the known changes in the hepatic rate of cholesterogenesis during pregnancy and lactation in vivo.

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Regulation of cholesterol synthesis in the liver and mammary gland of the lactating rat

Biochemical Journal ◽

10.1042/bj2120843 ◽

1983 ◽

Vol 212 (3) ◽

pp. 843-848 ◽

Cited By ~ 29

Author(s):

G F Gibbons ◽

C R Pullinger ◽

M R Munday ◽

D H Williamson

Keyword(s):

Mammary Gland ◽

Inverse Relationship ◽

Cholesterol Synthesis ◽

Reductase Activity ◽

Significant Decline ◽

High Fat ◽

Hmg Coa Reductase ◽

Lactating Mammary Gland ◽

Coa Reductase

The activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase; EC 1.1.1.34) in the lactating mammary gland of rats killed between 10:00 and 14:30 h was 2-3 times that in the livers of the same animals. In contrast, after injection of 3H2O in vivo, the rate of appearance of 3H in the cholesterol of the gland was much lower than that in the liver. In the mammary gland of virgin and non-lactating animals, the activity of HMG-CoA reductase was less than 10% of that of the lactating gland. The activity of HMG-CoA reductase in the lactating mammary gland was significantly (P less than 0.005) lower at midnight than at mid-day, and appeared to show an inverse relationship to the activity of the liver enzyme. However, there was no corresponding change in the incorporation of 3H into the gland cholesterol. Withdrawal of food for 6h had no effect on the activity of HMG-CoA reductase in the lactating mammary gland, but resulted in a significant decrease (P less than 0.005) in that of the liver. Starvation of lactating rats for 24h produced a significant decrease (P less than 0.005) in the activity of the enzyme in both organs. There was also a significant decline in the rate at which 3H2O was incorporated in vivo into the cholesterol of both organs (liver, P less than 0.05; gland, P less than 0.005). Giving a high-fat palatable diet together with chow to lactating animals led to a decline in HMG-CoA reductase activity in the mammary gland, but not in liver. This decrease in the gland was not accompanied by a corresponding decline in the apparent rate of cholesterol synthesis.

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The Cholesterol-Lowering Effect of Alisol Acetates Based on HMG-CoA Reductase and Its Molecular Mechanism

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4753852 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Fei Xu ◽

Hui Yu ◽

Cai Lu ◽

Jun Chen ◽

Wei Gu

Keyword(s):

Molecular Simulation ◽

Reductase Activity ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Hmg Coa Reductase ◽

Coa Reductase ◽

The Impact

This study measured the impact of alisol B 23-acetate and alisol A 24-acetate, the main active ingredients of the traditional Chinese medicine Alismatis rhizoma, on total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) levels of hyperlipidemic mice. The binding of alisol B 23-acetate and alisol A 24-acetate to the key enzyme involved in the metabolism of TC, 3-hydroxy-3-methylglutary-coenzyme A (HMG-CoA) reductase, was studied using the reagent kit method and the western blotting technique combined with a molecular simulation technique. According to the results, alisol acetates significantly lower the TC, TG, and LDL-C concentrations of hyperlipidemic mice, while raising HDL-C concentrations. Alisol acetates lower HMG-CoA reductase activity in a dose-dependent fashion, both in vivo and in vitro. Neither of these alisol acetates significantly lower the protein expression of HMG-CoA. This suggests that alisol acetates lower the TC level via inhibiting the activity of HMG-CoA reductase by its prototype drug, which may exhibit an inhibition effect via directly and competitively binding to HMG-CoA. The side chain of the alisol acetate was the steering group via molecular simulation.

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A relationship between the activities of hepatic lanosterol 14α-demethylase and 3-hydroxy-3-methylglutaryl-CoA reductase

Biochemical Journal ◽

10.1042/bj2500033 ◽

1988 ◽

Vol 250 (1) ◽

pp. 33-39 ◽

Cited By ~ 10

Author(s):

C Marco de la Calle ◽

W Hwang ◽

C R Pullinger ◽

G F Gibbons

Keyword(s):

Lipid Synthesis ◽

Relative Increase ◽

Rapid Decline ◽

Intragastric Administration ◽

Similar Time ◽

Hmg Coa Reductase ◽

Pre Treatment ◽

Coa Reductase ◽

Cytochrome P 450

At 1-2 h after intragastric administration of ketoconazole, a cytochrome P-450 inhibitor, to rats, there was a 50-60% decrease in the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Inhibition reached a maximum at 6-12 h after the drug was given, but after 24 h enzyme activity was stimulated by 60%. The rates of synthesis of hepatic non-saponifiable lipids in vivo showed a similar time-dependent pattern of change. During the first few hours after drug administration, the hepatic cytochrome P-450-dependent metabolism of lanosterol was suppressed in vivo. However, 24 h after treatment, this activity was stimulated, an effect which was also observed by pre-treatment of the rats with the drug for several days. Suppression of hepatic HMG-CoA reductase and lanosterol 14 alpha-demethylase activities was accompanied by a relative increase in the accumulation of labelled polar sterols in the liver in vivo. In the intestine, ketoconazole also resulted in a rapid decline in the rate of synthesis of non-saponifiable lipids and an inhibition of lanosterol 14 alpha-demethylation in vivo. However, in contrast with the liver, there was no stimulation of non-saponifiable lipid synthesis after 24 h.

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Solubility and Bioavailability Enhancement of Poorly Aqueous Soluble Atorvastatin:In Vitro,Ex Vivo, andIn VivoStudies

BioMed Research International ◽

10.1155/2014/463895 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Madhuri S. Rodde ◽

Ganesh T. Divase ◽

Tejas B. Devkar ◽

Avinash R. Tekade

Keyword(s):

Drug Release ◽

Dissolution Rate ◽

Ex Vivo ◽

Reductase Activity ◽

Polymer Concentration ◽

Water Soluble ◽

Hmg Coa Reductase ◽

Coa Reductase

The objective of this investigation was to improve the solubility of the poorly water soluble drug atorvastatin (ATR), using solid dispersion (SD) techniques, with Neem Gum (NG) as a hydrophilic carrier. The effects of the polymer concentration and method of preparation on the solubility and dissolution rate were studied. The results showed that the solubility of ATR increases with increasing NG concentration. However, dissolution rate of ATR from its SD was dependent on the method used to prepare SD. Anin vitrodrug release study revealed that the solvent evaporation technique is a more convenient and effective method of preparing SD than kneading method. The SD was characterized using DSC, SEM, and XRD study. Anin vivostudy was performed in which the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibition activity was measured. A significant reduction in HMG CoA reductase activity was observed with SD of ATR compared with the plain drug. Anex vivoabsorption study was carried out using modified apparatus developed in our laboratory. Thein vitrodrug release andin vivoandex vivostudies clearly demonstrated the potential of hydrophilic NG in enhancing the solubility, dissolution rate, and bioavailability of ATR.

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Novel Phytoconstituents of an Aqueous Pod Extract of Prosopis Cineraria (L.) Druce Attenuate Atherosclerotic Plaque and Hypercholesterolemia in Rabbits

10.21203/rs.3.rs-56652/v1 ◽

2020 ◽

Author(s):

Heera Ram ◽

Noopur Jaipal ◽

Pramod Kumar ◽

Jaykaran Charan ◽

Priya Kashyap ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

In Silico ◽

Reductase Activity ◽

Hmg Coa Reductase ◽

Prosopis Cineraria ◽

Oral Supplementation ◽

Coa Reductase ◽

Leading Compounds

Abstract Background and objectives: The pod of Prosopis cineraria traditionally used in several ailments and key component of traditional food recipe of the Panchkuta of western Rajasthan, India. The current study was targeted to assess ability of phytoconstituents of aqueous pod extract of Prosopis cineraria to inhibit HMG-CoA reductase activity and regress atherosclerotic plaque were investigated in in-vitro, in-vivo, and in-silico studies. Material and Methods: LCMS, GCMS, and FTIR analysis were used to characterize the phytoconstituents of the test extract. Accordingly, the in-vitro, in-vivo and in-silico assessments were performed by following the standard methods. Results: The phytochemical results shown the presence of cloprostenol, cinecromen, and dirithromycin as leading compounds. Accordingly, in-vivo assay of test extract shown HMG-CoA inhibition activity by 78.1 % (IC50 was 0.03 μg/ml). Hypercholesterolemia was induced in rabbits through oral supplementation of a high fat diet (21 % fat) with cholesterol powder supplementation. Administration of the test extract caused significant (𝑃 ≤ 0.001) improvement in the lipid profile and antioxidant levels in the test rabbits, relative to the hypercholesterolemic control rabbits. Subsequently, the reductions in the atherosclerotic plaque and improvement in lumen volume were pointedly observed in the treated groups. In-silico analyses of molecular docking and ADMET revealed significant interactions and druggability profile. Conclusion: It can be stated that the phytoconstituents of aqueous pod extract of Prosopis cineraria have the capacity to inhibit HMG-CoA reductase and regress the atherosclerotic plaque which may be beneficial to the treatment of hypercholesterolemia.

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Effects of diabetes on the expressed and total activities of 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver in vivo. Reversal by insulin treatment

Biochemical Journal ◽

10.1042/bj2300747 ◽

1985 ◽

Vol 230 (3) ◽

pp. 747-752 ◽

Cited By ~ 17

Author(s):

R A Easom ◽

V A Zammit

Keyword(s):

Activity Ratio ◽

Reductase Activity ◽

Active Form ◽

Fold Increase ◽

Total Activity ◽

Diabetic Rats ◽

Diurnal Rhythms ◽

Hmg Coa Reductase ◽

Coa Reductase

The expressed and total activities of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase (EC 1.1.1.34) were measured in microsomal fractions prepared from cold-clamped liver samples [Easom & Zammit (1984) Biochem. J. 220, 733-738] from control or insulin-treated diabetic animals. Streptozotocin-induced diabetes resulted in a marked decrease in total activity of HMG-CoA reductase and in the fraction of the enzyme in the active form, but appreciable effects were only observed in the liver of animals in which the blood glucose was above 20 mM. Intravenous infusion of insulin into diabetic rats resulted in a rapid (less than 20 min) and total dephosphorylation of the enzyme in vivo without any change in total activity. Longer-term (4 h) treatment with insulin (injected intraperitoneally) produced a rapid increase in expressed/total HMG-CoA reductase activity ratio to about 90%, followed, after a lag of 2-3 h, by a 5-6-fold increase in total activity. These observations are discussed with respect to the possible role of insulin in generating and maintaining the respective diurnal rhythms in total and in expressed/total HMG-CoA reductase activity ratio observed for normal animals in vivo [Easom & Zammit (1984) Biochem. J. 220, 739-745].

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Acute effects of starvation and treatment of rats with anti-insulin serum, glucagon and catecholamines on the state of phosphorylation of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase in vivo

Biochemical Journal ◽

10.1042/bj2410183 ◽

1987 ◽

Vol 241 (1) ◽

pp. 183-188 ◽

Cited By ~ 16

Author(s):

R A Easom ◽

V A Zammit

Keyword(s):

Intravenous Injection ◽

Activity Ratio ◽

Reductase Activity ◽

Active Form ◽

Fold Increase ◽

Total Activity ◽

Dark Phase ◽

Hmg Coa Reductase ◽

Coa Reductase

The fraction of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in the dephosphorylated (active) form in rat liver in vivo was measured after various experimental treatments of animals. Intraperitoneal injection of glucose (to raise serum insulin concentrations) into rats 4 h into the light phase (L-4) resulted in a transient (30 min) increase in the expressed (E)/total (T) activity ratio of HMG-CoA reductase without any change in total activity (obtained after complete dephosphorylation of the enzyme). Conversely, intravenous injection of guinea-pig anti-insulin serum into rats 4 h into the dark phase (D-4) significantly depressed the E/T ratio within 20 min. Intravenous injection of glucagon into normal rats at this time point did not affect the degree of phosphorylation of the enzyme, in spite of a 10-fold increase in hepatic cyclic AMP concentration induced by the hormone treatment. A 3-fold increase in the concentration of the cyclic nucleotide induced by adrenaline infusion was similarly ineffective in inducing any change in expressed or total activities of hepatic HMG-CoA reductase. However, when insulin secretion was inhibited, either by the induction of streptozotocin-diabetes or by simultaneous infusion of somatostatin, glucagon treatment was able to depress the expressed activity of HMG-CoA reductase (i.e. it increased the phosphorylation of the enzyme). Therefore insulin appears to have a dominant role in the regulation of the phosphorylation state of hepatic HMG-CoA reductase. In apparent corroboration of this suggestion, short-term 4 h food deprivation of animals before D-4 resulted in a marked decrease in the E/T activity ratio of reductase, which was not affected further by an additional 8 h starvation. By contrast, the total activity of the enzyme was not significantly affected by 4 h starvation, but was markedly diminished after 12 or 24 h starvation. Longer-term starvation also produced a chronic increase in the degree of phosphorylation of the enzyme. These results are discussed in relation to the role of reversible phosphorylation in the control of hepatic HMG-CoA reductase activity in vivo.

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