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Biomedical subjects

S Balasubramaniam

Publications and source records attributed to S Balasubramaniam.

At least 73 records · Page 4Linked to original sources
PubMed1979

Acyl-coenzyme A--cholesterol acyltransferase activity in human liver.

1. In the presence of CoA and ATP, human liver microsomes catalyse the incorporation of [14C]oleate or [14C]cholesterol into cholesteryl oleate, thus demonstrating the presence of acyl-coenzyme A-cholesterol acyltransferase (cholesterol acyltransferase) in human liver. 2. The enzyme has properties similar to those of rat liver enzyme and with both the concentration of endogenous cholesterol in the microsomal fraction is adequate to support a constant initial rate of esterification. However, unlike the rat liver enzyme, the human cholesterol acyltransferase does not efficiently utilize added cholesterol as substrate. 3. The activity of cholesterol acyltransferase in human liver was 25% of that measured in rat liver under similar conditions of assay.

Acyltransferases↗
PubMed1978

The submicrosomal localization of acyl-coenzyme A-cholesterol acyltransferase and its substrate, and of cholesteryl esters in rat liver.

To determine the submicrosomal distribution of acyl-CoA-cholesterol acyltransferase and of cholesteryl esters, the microsomal fraction and the digitonin-treated microsomal preparation of rat liver were subjected to analytical centrifugation on sucrose density gradients. With untreated microsomal fractions the distribution profile and the median density of acyl-CoA-cholesterol acyltransferase were very similar to those of RNA. This is in contrast with hydroxymethylglutaryl-CoA reductase and cholesterol 7alpha-hydroxylase, which are confined to endoplasmic reticulum membranes with low ribosomal coating. In digitonin-treated microsomal preparations activity of acyl-CoA-cholesterol acyltransferase was not detectable. The labelling of untreated microsomal fractions with trace amounts of [(14)C]cholesterol followed by subfractionation of the labelled microsomal fraction showed that the specific radioactivity of cholesteryl esters obtained in vitro by the various subfractions was similar with all subfractions but different from the specific radioactivity of the 7alpha-hydroxycholesterol obtained in vitro by the same subfraction. These results demonstrate the existence of two pools of cholesterol confined to membranes from the endoplasmic reticulum, one acting as substrate for cholesterol 7alpha-hydroxylase and the other acting as substrate for acyl-CoA-cholesterol acyltransferase. The major part of cholesteryl esters present in both untreated and digitonin-treated microsomal fractions was distributed at densities similar to those of membranes from the smooth endoplasmic reticulum and at densities lower than those of smooth membranes from Golgi apparatus. The ratio of the concentrations of non-esterified to esterified cholesterol in the subfractions from both untreated and digitonin-treated microsomal fractions was highest at the maximum distribution of plasma membranes.

Acyl Coenzyme A↗
PubMed1978

On the mechanism for the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, of cholesterol 7alpha-hydroxylase and of acyl-coenzyme A:cholesterol acyltransferase by free cholesterol.

The administration of mevalonic acid to rats by intravenous injection resulted in a dose- and time-dependent increase in the activity of cholesterol 7alpha-hydroxylase in the liver microsomal fraction, a decrease in the microsomal activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and no significant change in the activity of acyl-coenzyme A:cholesterol acyltransferase or in the concentration of free and of esterified cholesterol in the liver microsomal fraction. However, the increased hepatic cholesterogenesis that follows the injection of mevalonic acid resulted in an increase of the size of the intracellular pool of cholesterol that is in the environment of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acts as substrate for cholesterol 7alpha-hydroxylase. The administration of mevalonic acid to rats by stomach tube resulted in an increase in the activity of cholesterol 7alpha-hydroxylase and of acyl-coenzyme A:cholesterol acyltransferase and in the concentration of cholesterol esters in the liver microsomal fraction, while there was a considerable decrease in the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Acyltransferases↗
PubMed1977

Lipoprotein-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesteryl ester metabolism in the adrenal gland of the rat.

In the adrenal gland of the rat, the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme of cholesterol synthesis, is shown to be regulated by cholesteerol carried in plasma lipoproteins. When plasma cholesterol levels were lowered 90% by administration of the drug 4-aminopyrazolopyrimidine, the cholesteryl ester content of the adrenal gland declined by more than 90% and this was associated with a 150- to 200-fold increase in the activity of adrenal 3-hydroxy-3-methylglutaryl coenzyme A reductase and a 30-fold increase in cholesterol synthesis from [14C]acetate. The subsequent intravenous infusion of cholesterol contained in either rat or human high density or low density lipoproteins restored the adrenal content of cholesteryl esters and reduced the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase to basal levels. The depletion of adrenal cholesteryl esters and the enhancement in the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase that occurred in the 4-aminopyrazolopyrimidine-treated rat required the action of adrenocorticotropic hormone (ACTH) since neither was observed when ACTH secretion was blocked by administration of dexamethasone. The current data indicate that the low rate of cholesterol synthesis normally observed in the rat adrenal gland is due to a suppression of the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase that is mediated by plasma lipoproteins.

Adenine↗
PubMed1977

Regulation of cholesterol synthesis in rat adrenal gland through coordinate control of 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase activities.

The activities of cytosolic 3-hydroxy-3-methylglutaryl coenzyme A synthase [3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase (CoA-acylating), EC 4.1.3.5] and microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase[mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], two sequential enzymes in the cholesterol biosynthetic pathway, were shown to be regulated coordinately in the adrenal gland of the rat. When the plasma cholesterol level was lowered by administration of 4-aminopyrazolopyrimidine, a treatment known to enhance cholesterol synthesis in the adrenal, synthase activity in the gland rose by 14- to 29-fold and reductase activity rose by 50- to 100-fold. The subsequent intravenous infusion of low density lipoprotein restored the plasma cholesterol level and suppressed synthase and reductase activities in parallel. The activities of adrenal 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase were also shown to exhibit a coordinate pattern of diurnal variation with peaks in both enzymes achieved at the mid-point of the dark cycle. The activity of adrenal acetoacetyl coenzyme A thiolase (acetyl CoA acetyltransferase; acetyl-CoA:acetyl-CoA C-acetyltransferase, EC 2.3.1.9), the enzyme preceding the synthase in the cholesterol biosynthetic pathway, and the activity of adrenal mevalonate kinase (ATP:mevalonate 5-phosphotransferase, EC 2.7.1.36), the enzyme following the reductase, were not enhanced by cholesterol deprivation, and neither exhibited a pattern of diurnal variation. The coordinate control of 3-hydroxy-3-methylglutaryl CoA synthase and reductase in rat adrenal gland provides a model system to study the biochemical mechanism for the regulation of cholesterol synthesis in a tissue that uses cholesterol for the synthesis of steroid hormones.

Acetyl-CoA C-Acetyltransferase↗
PubMed1976

The role of glucocorticoids in the regulation of the diurnal rhythm of hepatic beta-hydroxy-beta-methylglutaryl-coenzyme A reductase and cholesterol 7 alpha-hydroxylase.

The microsomal activities of the hepatic enzymes hydroxymethylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase exhibit a diurnal rhythm with maximum activities observed during the dark period and minimum activities around noon (12:00h). This diurnal rhythm was maintained for both enzymes after adrenalectomy, but the amplitude of variation for the activity of both enzymes was greatly decreased. A single injection of cortisol administered to adrenalectomized rats 3h before the expected maximum in enzyme activity resulted in a twofold increase in the activity of both enzymes 3h later, at values similar to those observed for control rats killed at the same time. This response appeared to require protein synthesis, since it was blocked by actinomycin D. However, the administration of cortisol to adrenalectomized rats 3 h before the expected minimum did not result in significant change in the activity of hydroxymethylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase 3 h later. Kinetic studies of cholic acid metabolism in vivo demonstrated that adrenalectomy results in a significant decrease in the rate of synthesis of cholic acid and a considerable decrease in the pool size of cholic acid and its metabolic products. Treatment of adrenalectomized rats with cortisol increased the rate oonsistent with the effects of adrenalectomy and cortisol treatment on the activity of cholesterol 7alpha-hydroxylase.

Adrenalectomy↗
PubMed1976

The effect of portacaval anastomosis on plasma lipoprotein metabolism in rats.

1. The effect of portacaval anastomosis on the metabolism of plasma lipoproteins was investigated in rats. 2. When compared with sham-operated pair-fed controls, plasma high density lipoprotein cholesterol concentration was decreased, plasma low density lipoprotein cholesterol concentration was increased and plasma total cholesterol concentration was unchanged in the portacaval anastomosis rats. Maximal incorporation of [14C]leucine into the total circulating mass of protein was decreased in the very low density lipoprotein and high density lipoprotein fractions and, possibly, in the low density lipoprotein fraction, but there was no change in maximal incorporation into albumin. It is concluded that portacaval anastomosis diminishes the rate of synthesis of high density lipoprotein and very low density lipoprotein proteins and, possibly, of low density lipoprotein proteins.

Animals↗
PubMed1976

Effect of portacaval anastomosis on the activities of hepatic enzymes related to cholesterol and bile acid metabolism in rats.

1. The effect of a portacaval anastomosis on the activities of hepatic enzymes related to cholesterol metabolism was investigated in rats. 2. Portacaval anastomosis led to a fall in body weight and liver weight/body weight ratio, and to a rise in the activities of hydroxymethylglutaryl-CoA reductase and cholesterol 7alpha-hydroxylase per g of liver. The net effect was to maintain a normal activity of both enzymes per 100 g of rat. Diurnal rhythm in the activities of both enzymes was maintained after portacaval anastomosis. 3. The rate of excretion of total bile acids, per 100 g of rat, in bile fistula rats was not significantly decreased by portacaval anastomosis.

Animals↗
PubMed1976

Evidence for regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol synthesis in nonhepatic tissues of rat.

The adenine analogue 4-aminopyrazolopyrimidine has been reported previously to reduce the hepatic secretion of plasma lipoproteins in rats, thereby lowering the plasma cholesterol level. In the current studies, reduction of the plasma cholesterol level by 90% in rats through the administration of aminopyrazolopyrimidine was found to be associated with a 5- to 30-fold increase in the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC1.1.1.34] in kidney and lung. In both tissues, the enhanced activity of this microsomal enzyme was associated with a 3-fold elevation in the rate of cholesterol synthesis from either [14C]acetate or [14C]octanoate. Comparable increases were not observed in the activities of several other microsomal enzymes or in the rates of [14C]acetate incorporation into saponifiable lipids or CO2. When administration of 4-aminopyrazolopyrimidine was terminated, plasma cholesterol levels rose and 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity declined in the kidney in a reciprocal manner. These data are consistent with the hypothesis that the low levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and cholesterol synthesis that are normally observed in certain nonhepatic tissues of the rat are due to an active form of feedback regulation mediated by cholesterol carried in plasma lipoproteins.

Acetates↗
PubMed1975

The substrate for cholesterol 7alpha-hydroxylase.

The rates of incorporation of (14C) cholesterol into cholesteryl esters and 5-cholestene-3beta,7alpha-diol (7alpha-hydroxycholesterol) by rat liver microsomes, measured under conditions in which esterification and 7alpha-hydroxylation are varied independently, indicated that cholesterol is the substrate for cholesterol 7alpha-hydroxylase. The specific activities of cholesteryl esters and 7alpha-hydroxycholeste ol in incubations of microsomes labelled with (14C)cholesterol in vitro or in vivo suggest that 7alpha-hydroxycholesterol and esterified cholesterol are not derived from the same pool of free cholesterol.

Adenosine Triphosphate↗