scholarly journals The absolute rate of cholesterol biosynthesis in monocyte-macrophages from normal and familial hypercholesterolaemic subjects

1984 ◽  
Vol 219 (2) ◽  
pp. 461-470 ◽  
Author(s):  
D D Patel ◽  
C R Pullinger ◽  
B L Knight
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Cholesterol Biosynthesis ◽  
Specific Radioactivity ◽  
Density Lipoprotein ◽  
Cellular Protein ◽  
True Rate ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
In Cells

The true rate of cholesterogenesis in cultured monocyte-macrophages was determined from the incorporation of [2-14C]acetate into cholesterol, using the desmosterol (cholesta-5,24-dien-3 beta-ol) that accumulated in the presence of the drug triparanol to estimate the specific radioactivity of the newly formed sterols. It was shown that this procedure could be successfully adapted for use with cultured monocytes despite the accumulation of other unidentified biosynthetic intermediates. In cells maintained in 20% (v/v) whole serum approx. 25% of the sterol carbon was derived from exogenous acetate. Cholesterol synthesis was as high in normal cells as in cells from homozygous familial hypercholesterolaemic (FH) subjects and accounted for 50% of the increase in cellular cholesterol. The addition of extra low-density lipoprotein (LDL) reduced cholesterol synthesis, apparently through a decrease in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). When incubated in lipoprotein-deficient serum some cells did not survive, but those that remained showed a normal increase in protein content; the amount of cellular protein and cholesterol in each well did not increase and cholesterol synthesis was reduced by over 80%. HMG-CoA reductase activity fell less dramatically and the proportion of sterol carbon derived from exogenous acetate increased, suggesting that the low rate of cholesterogenesis with lipoprotein-deficient serum was due to a shortage of substrate. The results indicate that under normal conditions monocyte-macrophages obtain cholesterol from endogenous synthesis rather than through receptor-mediated uptake of LDL, and that synthesis together with non-saturable uptake of LDL provides the majority of the cholesterol required to support growth.

scholarly journals Regulation of hepatic cholesterol biosynthesis. Effects of a cytochrome P-450 inhibitor on the formation and metabolism of oxygenated sterol products of lanosterol

1989 ◽  
Vol 264 (2) ◽  
pp. 495-502 ◽  
Author(s):  
J Iglesias ◽  
G F Gibbons
Keyword(s):  
Reductase Activity ◽  
Cholesterol Biosynthesis ◽  
Mevalonic Acid ◽  
Subcellular Fractions ◽  
Hmg Coa Reductase ◽  
Hepatocyte Cultures ◽  
C 32 ◽  
Lanosterol Demethylase ◽  
Cholesterol Precursor ◽  
Coa Reductase

The involvement of oxygenated cholesterol precursors in the regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was studied by examining the effect of ketoconazole on the metabolism of mevalonic acid, lanosterol and the lanosterol metabolites, lanost-8-ene-3 beta,32-diol,3 beta-hydroxylanost-8-en-32-al and 4,4-dimethylcholesta-8,14-dien-3 beta-ol, in liver subcellular fractions and hepatocyte cultures. Inhibition of cholesterol synthesis from mevalonate by ketoconazole at concentrations up to 30 microM was due exclusively to a suppression of cytochrome P-450LDM (LDM = lanosterol demethylase) activity, resulting in a decreased rate of lanosterol 14 alpha-demethylation. No enzyme after the 14 alpha-demethylase step was affected. When [14C]mevalonate was the cholesterol precursor, inhibition of cytochrome P450LDM was accompanied by the accumulation of several labelled oxygenated sterols, quantitatively the most important of which was the C-32 aldehyde derivative of lanosterol. There was no accumulation of the 24,25-oxide derivative of lanosterol, nor of the C-32 alcohol. Under these conditions the activity of HMG-CoA reductase declined. The C-32 aldehyde accumulated to a far greater extent when lanost-8-ene-3 beta,32-diol rather than mevalonate was used as the cholesterol precursor in the presence of ketoconazole. With both precursors, this accumulation was reversed at higher concentrations of ketoconazole in liver subcellular fractions. A similar reversal was not observed in hepatocyte cultures.

Effect of glucose or fructose feeding on cholesterol synthesis in diabetic animals

1985 ◽  
Vol 249 (5) ◽  
pp. G634-G641 ◽  
Author(s):  
K. R. Feingold ◽  
A. H. Moser
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Active Form ◽  
Diabetic Rats ◽  
Hepatic Cholesterol ◽  
Hmg Coa Reductase ◽  
Hepatic Cholesterol Synthesis ◽  
Streptozotocin Induced Diabetes ◽  
Intestinal Hypertrophy ◽  
Coa Reductase

Previous studies have demonstrated that cholesterol synthesis is increased twofold in the small intestines of rats with streptozotocin-induced diabetes. The purpose of the present study was to determine the effect of adding glucose or fructose to standard rat chow on cholesterol synthesis in control and diabetic rats. In control rats a 25% glucose or fructose diet fed for 21 days markedly inhibited hepatic cholesterol synthesis in the liver. In contrast, in diabetic animals only fructose inhibited hepatic cholesterol synthesis. In both control and diabetic animals the addition of these simple sugars to the diet did not markedly alter extrahepatic cholesterol synthesis. The enhancement of small intestinal cholesterol synthesis observed in diabetic animals was present regardless of the dietary manipulations. Further studies demonstrated that the addition of smaller concentrations of fructose (10%) to standard rat chow decreased hepatic cholesterol synthesis in both control and diabetic rats. Similarly the addition of fructose to the diet of control and diabetics for a period as short as 2 days was also sufficient to inhibit hepatic cholesterol synthesis. In both control and diabetic animals, fructose feeding decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity but did not alter the percentage of HMG-CoA reductase in the active form. Finally, the intestinal hypertrophy and stimulation of intestinal cholesterogenesis that are characteristic of streptozotocin-induced diabetes occurred when either glucose or fructose was the sole caloric source.

scholarly journals Antihyperlipidemic and Antioxidative Potentials of Onion (Allium cepaL.) Extract Fermented with a NovelLactobacillus caseiHD-010

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Woong-Suk Yang ◽  
Jin-Chul Kim ◽  
Jae Yong Lee ◽  
Cheorl-Ho Kim ◽  
Cher-Won Hwang
Keyword(s):  
Reductase Activity ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Treated Group ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Control Group ◽  
Hmg Coa Reductase ◽  
Onion Extract ◽  
Coa Reductase

The purpose of this study was to investigate antihyperlipidemic and antioxidative potentials of onion (Allium cepaL.) extract fermented with a novelLactobacillus caseiHD-010. In general, fermented onion extract is used for its antioxidative activity (ORAC), inhibitory effect on adipocytes differentiation, quercetin contents, and antihyperlipidemic activities. However, the effect of fermented onion extract on hyperlipidemia after oral administration using ApoE-deficient mice has not been reported yet. To understand the effect of fermented onion extract on hyperlipidemia, we used benzafibrate (10 mg/kg, bw/day) as a positive control in the present study. Serum was collected every week to analyze levels of low density lipoprotein (LDL), high density lipoprotein (HDL), triglyceride (TG), and cholesterol, 3-hydroxy-3-methylgutaryi-CoA (HMG-CoA) reductase activity, and cholesterol ester transport protein (CETP) activity. In the fermented onion-treated group, HDL level was significantly increased while levels of TG and LDL were significantly decreased compared to those in the control group. In addition, the inhibition activity of HMG-CoA reductase was increased 20% in the fermented onion-treated group at 100 mg/kg. CETP activity has been observed to be significantly inhibited in the fermented onion-treated groups compared to that in the control group. These results suggest that fermented onion has a preventive/therapeutic effect on hyperlipidemic disease. It might have potential to be developed as a functional food.

Acetoacetyl-CoA ligase activity in the isolated rat hepatocyte: Effects of 25-hydroxycholesterol and high density lipoprotein

1987 ◽  
Vol 7 (3) ◽  
pp. 217-224 ◽  
Author(s):  
Gail A. Wong ◽  
James D. Bergstrom ◽  
John Edmond
Keyword(s):  
High Density Lipoprotein ◽  
Reductase Activity ◽  
Density Lipoprotein ◽  
High Density ◽  
Sterol Synthesis ◽  
Hmg Coa Reductase ◽  
Coa Ligase ◽  
Fold Induction ◽  
Activity State ◽  
Coa Reductase

The activity of acetoacetyl-CoA (AcAc-CoA) ligase (E.C.6.2.1.16) in hepatocytes from rats was shown to be the same as the activity in homogenates of their livers. In hepatocytes treated with 25-hydroxycholesterol, AcAc-CoA ligase, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and rates of sterol synthesis were substantially decreased. Hepatocytes treated with high density lipoprotein (HDL) exhibited a 2 to 4 fold induction of HMG-CoA reductase activity; however an accompanying increase in AcAc-CoA ligase activity and the rate of cholesterol synthesis was not observed. We conclude (a) that increases in the activity of HMG-CoA reductase when mediated by HDL in hepatocytes do not result in a corresponding change in the capacity for sterol synthesis and (b) that changes in the activity state of HMG-CoA reductase can be dissociated from that of AcAc-CoA ligase.

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

1983 ◽  
Vol 212 (3) ◽  
pp. 843-848 ◽  
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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