scholarly journals Drugs affecting the synthesis of glycerides and phospholipids in rat liver. The effects of clofibrate, halofenate, fenfluramine, amphetamine, cinchocaine, chlorpromazine, demethylimipramine, mepyramine and some of their derivatives

1975 ◽  
Vol 148 (3) ◽  
pp. 461-469 ◽  
Author(s):  
D N Brindley ◽  
M Bowley
Keyword(s):  
Rat Liver ◽  
Inhibitory Effect ◽  
Diacylglycerol Acyltransferase ◽  
Major Effect ◽  
Glycerol Phosphate ◽  
Liver Slices ◽  
Phosphatidate Phosphohydrolase ◽  
Marked Accumulation ◽  
Glycerolipid Synthesis ◽  
Phosphatidylcholine Synthesis

The effects on glycerolipid synthesis of a series of compounds including many drugs were investigated in cell-free preparations and slices of rat liver. p-Chlorobenzoate, p-chlorophenoxyisobutyrate, halofenate, D-amphetamine, adrenaline, procaine and N-[2-(4-chloro-3-sulphamoylbenzoyloxy)ethyl]norfenfluramine had little inhibitory effect on any of the systems investigated. Two amphiphilic anions, clofenapate and 2-(p-chlorophenyl)-2-(m-trifluoromethylphenoxy)acetate, both inhibited glycerol phosphate acyltransferase and diacylglycerol acyltransferase at approx. 1.6 and 0.7 mm respectively. Clofenapate (1 mm) also inhibited the incorporation of glycerol into lipids by rat liver slices without altering the relative proportions of the different lipids synthesized. The amphilic amines, mepyramine, fenfluramine, norfenfluramine, hydroxyethylnorfenfluramine, N-(2-benzoyloxyethyl)norfenfluramine, cinchocaine, chlorpromazine and demethylimipramine inhibited phosphatidate phosphohydrolase by 50% at concentrations between 0.2 and 0.9 mm. The last four compounds inhibited glycerol phosphate acyltransferase by 50% at concentrations between 1 and 2.6 mm. None of the amines examined appeared to be an effective inhibitor of diacylglycerol acyltransferase. Norfenfluramine, hydroxyethylnorfenfluramine and N-(2-benzoyloxyethyl)norfenfluramine produced less inhibition of glycerol incorporation into total lipids than was observed with equimolar clofenapate. The major effect of these amines in liver slices was to inhibit triacylglycerol and phosphatidylcholine synthesis and to produce a marked accumulation of phosphatidate. The results are discussed in terms of the control of glycerolipid synthesis. They partly explain the observed effects of the various drugs on lipid metabolism. The possible use of these compounds as biochemical tools with which to investigate the reactions of glycerolipid synthesis is considered.

scholarly journals The effect of chronic diabetes, induced by streptozotocin, on the activities of some enzymes of glycerolipid synthesis in rat liver

1977 ◽  
Vol 168 (2) ◽  
pp. 147-153 ◽  
Author(s):  
P H Whiting ◽  
M Bowley ◽  
R G Sturton ◽  
P H Pritchard ◽  
D N Brindley ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Single Dose ◽  
Rat Liver ◽  
Diacylglycerol Acyltransferase ◽  
Diabetic Rats ◽  
Glycerol Phosphate ◽  
Choline Phosphotransferase ◽  
Phosphatidate Phosphohydrolase ◽  
Glycerolipid Synthesis ◽  
Increased Activity

1. Rats were injected with a single dose of 35mg of streptozotocin/kg body wt. They exhibited a diabetes that was characterized by glycosuria, polyuria, polydipsia, hyperphagia, hyperglycaemia, increased concentrations of unesterified fatty acids, glycerol and triacylglycerols in the serum and an increased activity of glucose 6-phosphatase in the liver. 2. After 10 weeks the hepatic activities of the microsomal glycerol phosphate acyltransferase, phosphatidate phosphohydrolase, phosphatidate cytidylyltransferase, diacylglycerol acyltransferase, choline phosphotransferase, CDP-diacylglycerolx—inositol phosphatidyltransferase and the soluble phosphatidate phosphohydrolase were measured. 3. The only significant changes were an increase in the activity of the soluble phosphatidate phosphohydrolase and a decrease in that of the CDP-diacylglycerol—inositol phosphatidyltransferase in the diabetic rats. 4. These results are discussed in relation to the control of glycerolipid synthesis.

EFFECTS OF ALIPHATIC ALCOHOLS ON THE METABOLISM OF GLUCOSE AND FRUCTOSE IN RAT LIVER SLICES

1963 ◽  
Vol 41 (3) ◽  
pp. 793-803 ◽  
Author(s):  
Edward Majchrowicz ◽  
J. H. Quastel
Keyword(s):  
Rat Liver ◽  
Liver Slice ◽  
Inhibitory Effect ◽  
Aliphatic Alcohols ◽  
Isotopic Dilution ◽  
Acetyl Coa ◽  
Radioactive Carbon ◽  
Liver Slices ◽  
The Difference ◽  
Ethanol Ethanol

Ethanol, at concentrations up to 3 mM, whilst having little inhibitory effect on the production of respiratory CO2of rat liver slices, has a marked suppressing action on the formation of labelled CO2from labelled glucose. The suppression of C14O2formation by ethanol from radioactive glucose is independent of the concentration of the latter and amounts to 57% with 3 mM ethanol after 1 hour's incubation. The results are consistent with the conclusion that ethanol gives rise more rapidly than glucose to acetyl CoA and that the large suppressing action of ethanol in rat liver slices is due to isotopic dilution of labelled acetyl CoA derived from the labelled sugars with the unlabelled acetyl CoA derived from ethanol. Ethanol exercises a larger inhibition of the rate of C14O2formation from glucose-6-C14than from glucose-1-C14. The difference between the effects of ethanol on C14O2formation from glucose-1-C14and glucose-6-C14is presumably due to operation of the hexosemonophosphate shunt.The higher aliphatic alcohols have about the same diminishing effect on C14O2formation from glucose-U-C14and fructose-U-C14as does ethanol. This observation may also be a consequence of dilution of labelled acetyl CoA derived from the sugars by unlabelled acetyl CoA coming from the added alcohol. Incorporation of radioactive carbon from the labelled sugars into liver proteins and lipids is inhibited by ethanol and higher aliphatic alcohols, and the inhibitions are similar in magnitude to those of C14O2formation. These may be accounted for by isotopic dilution. The amounts of C14incorporated into lipids and proteins from radioactive glucose and fructose are small, being about 1/10th of that appearing in the CO2.The higher aliphatic alcohols suppress total CO2formation during rat liver slice respiration much more than does ethanol at equivalent concentrations.

scholarly journals The effects of acute ethanol feeding and of chronic benfluorex administration on the activities of some enzymes of glycerolipid synthesis in rat liver and adipose tissue

1977 ◽  
Vol 166 (3) ◽  
pp. 639-642 ◽  
Author(s):  
P H Pritchard ◽  
M Bowley ◽  
S L Burditt ◽  
J Cooling ◽  
H P Glenny ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Rat Liver ◽  
Energy Content ◽  
Phosphatidate Phosphohydrolase ◽  
Acute Ethanol ◽  
Ethanol Feeding ◽  
Glycerolipid Synthesis

Rats were treated for 5 days with benfluorex [1-(3-trifluoromethylphenyl)-2-[N-(2-benzoyloxyethyl)amino]propane] or with suspending medium (controls). They were then intubated with an acute intoxicating dose of ethanol or with glucose of equivalent energy content. Treatment of the control rats with ethanol specifically increases the hepatic activity of the soluble phosphatidate phosphohydrolase by about 5-fold in 6 h. The equivalent increase for the benfluorex-treated rats were about 2-fold. The results are discussed in relation to the effects of ethanol and benfluorex on glycerolipid synthesis.

scholarly journals Problems encountered in measuring the activity of phosphatidate phosphohydrolase

1978 ◽  
Vol 171 (1) ◽  
pp. 263-266 ◽  
Author(s):  
R G Sturton ◽  
D N Brindley
Keyword(s):  
Rat Liver ◽  
Glycerol Phosphate ◽  
Phosphate Release ◽  
Phosphatidate Phosphohydrolase

The measurement of phosphate release from phosphatidate overestimates the microsomal activity of phosphatidate phosphohydrolase from rat liver, since phosphate is also produced via the glycerol phosphate that results from the deacylation of phosphatidate. The determination of phosphate production can be a reliable assay for the soluble phosphatidate phosphohydrolase in rat liver, because the glycerol phosphate formed is not hydrolysed under the conditions used.

scholarly journals Tritium isotope effects in the measurement of the glycerol phosphate and dihydroxyacetone phosphate pathways of glycerolipid biosynthesis in rat liver

1972 ◽  
Vol 130 (4) ◽  
pp. 1003-1012 ◽  
Author(s):  
Ray Manning ◽  
David N. Brindley
Keyword(s):  
Neutral Lipid ◽  
Rat Liver ◽  
Isotope Effects ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Dihydroxyacetone Phosphate ◽  
Glycerol Concentration ◽  
Glycerol Phosphate ◽  
Experimental Conditions ◽  
Liver Slices

1. Rat liver slices were employed to study the relative rates of incorporation of a mixture of [2-3H]- or [1,3-3H]-glycerol and [1-14C]glycerol into lipids. 2. With 0.1mm-glycerol approx. 82% of the newly synthesized lipid, calculated from 14C incorporation, was present as neutral lipid, 13% as phosphatidylcholine and 5% as phosphatidylethanolamine. Increasing the glycerol concentration to 40mm caused a decrease in the percentage of neutral lipid to 59% and a corresponding increase in the percentage of phosphatidylcholine to 36% of the newly synthesized lipid. 3. The (d.p.m. of 2-3H)/(d.p.m. of 1-14C) ratio in glycerolipid was considerably higher than that in precursor glycerol throughout the range of experimental conditions. In contrast the incorporation of a mixture of [1,3-3H]glycerol and [1-14C]glycerol into lipid occurred with little or no change in the 3H/14C ratio. 4. Respiring rat liver mitochondria were found to oxidize a mixture of sn-[2-3H]- and sn-[1-14C]-glycerol 3-phosphate with a resultant increase in the 3H/14C ratio of the remaining sn-glycerol 3-phosphate. This increase is due to a 3H isotope effect of the mitochondrial sn-glycerol 3-phosphate dehydrogenase (EC 1.1.99.5), which discriminates against sn-[2-3H]glycerol 3-phosphate during oxidation. 5. A method is described for the simultaneous determination of the relative contributions of the glycerol phosphate and dihydroxyacetone phosphate pathways of glycerolipid biosynthesis in rat liver slices. The method involves measurement of the (d.p.m. of 2-3H)/(d.p.m. of 1-14C) ratio in both sn-glycerol 3-phosphate and glycerolipid after incubation of rat liver slices with a mixture of [2-3H]glycerol and [1-14C]glycerol for various times. 6. By using this method it was shown that 40–50% of the glycerol incorporated into lipid by rat liver slices proceeded via the sn-glycerol 3-phosphate pathway and 50–60% was incorporated via dihydroxyacetone phosphate.

EFFECTS OF ALIPHATIC ALCOHOLS ON THE METABOLISM OF GLUCOSE AND FRUCTOSE IN RAT LIVER SLICES

1963 ◽  
Vol 41 (1) ◽  
pp. 793-803 ◽  
Author(s):  
Edward Majchrowicz ◽  
J. H. Quastel
Keyword(s):  
Rat Liver ◽  
Liver Slice ◽  
Inhibitory Effect ◽  
Aliphatic Alcohols ◽  
Isotopic Dilution ◽  
Acetyl Coa ◽  
Radioactive Carbon ◽  
Liver Slices ◽  
The Difference ◽  
Ethanol Ethanol

Ethanol, at concentrations up to 3 mM, whilst having little inhibitory effect on the production of respiratory CO2of rat liver slices, has a marked suppressing action on the formation of labelled CO2from labelled glucose. The suppression of C14O2formation by ethanol from radioactive glucose is independent of the concentration of the latter and amounts to 57% with 3 mM ethanol after 1 hour's incubation. The results are consistent with the conclusion that ethanol gives rise more rapidly than glucose to acetyl CoA and that the large suppressing action of ethanol in rat liver slices is due to isotopic dilution of labelled acetyl CoA derived from the labelled sugars with the unlabelled acetyl CoA derived from ethanol. Ethanol exercises a larger inhibition of the rate of C14O2formation from glucose-6-C14than from glucose-1-C14. The difference between the effects of ethanol on C14O2formation from glucose-1-C14and glucose-6-C14is presumably due to operation of the hexosemonophosphate shunt.The higher aliphatic alcohols have about the same diminishing effect on C14O2formation from glucose-U-C14and fructose-U-C14as does ethanol. This observation may also be a consequence of dilution of labelled acetyl CoA derived from the sugars by unlabelled acetyl CoA coming from the added alcohol. Incorporation of radioactive carbon from the labelled sugars into liver proteins and lipids is inhibited by ethanol and higher aliphatic alcohols, and the inhibitions are similar in magnitude to those of C14O2formation. These may be accounted for by isotopic dilution. The amounts of C14incorporated into lipids and proteins from radioactive glucose and fructose are small, being about 1/10th of that appearing in the CO2.The higher aliphatic alcohols suppress total CO2formation during rat liver slice respiration much more than does ethanol at equivalent concentrations.

scholarly journals The activities of lipoprotein lipase and of enzymes involved in triacylglycerol synthesis in rat adipose tissue. Effects of starvation, dietary modification and of corticotropin injection

1981 ◽  
Vol 200 (2) ◽  
pp. 285-294 ◽  
Author(s):  
N Lawson ◽  
A D Pollard ◽  
R J Jennings ◽  
M I Gurr ◽  
D N Brindley
Keyword(s):  
Adipose Tissue ◽  
Lipoprotein Lipase ◽  
Corn Oil ◽  
Diacylglycerol Acyltransferase ◽  
Dietary Modification ◽  
Dihydroxyacetone Phosphate ◽  
Glycerol Phosphate ◽  
Triacylglycerol Synthesis ◽  
Phosphatidate Phosphohydrolase ◽  
Starch Diet

1. The effects of dietary modification, including starvation, and of corticotropin injection on the activities of acyl-CoA synthetase, glycerol phosphate acyltransferase, dihydroxyacetone phosphate acyltransferase, phosphatidate phosphohydrolase, diacylglycerol acyltransferase and lipoprotein lipase were measured in adipose tissue. 2. Lipoprotein lipase activities in heart were increased and those in adipose tissue were decreased when rats were fed on diets enriched with corn oil or beef tallow rather than with sucrose or starch. The lipoprotein lipase activity was lower in the adipose tissue of rats fed on the sucrose rather than on the starch diet. 3. Rats fed on the beef tallow diet had slightly higher activities of the total glycerol phosphate acyltransferase in adipose tissue than did rats fed on the sucrose or starch diet. The diacylglycerol acyltransferase and the mitochondrial glycerol phosphate acyltransferase activities were higher for the rats fed on the tallow diet than for those fed on the corn-oil diet. 4. Starvation significantly decreased the activities of lipoprotein lipase (after 24 and 48 h), acyl-CoA synthetase (after 24 h) and of the mitochondrial glycerol phosphate acyltransferase and the N-ethylmaleimide-insensitive dihydroxyacetone phosphate acyltransferase (after 48 h) in adipose tissue. The activities of the microsomal glycerol phosphate acyltransferase, diacylglycerol acyltransferase and the soluble phosphatidate phosphohydrolase were not significantly changed after 24 or 48 h of starvation. 5. The activities of lipoprotein lipase and phosphatidate phosphohydrolase in adipose tissue were decreased 15 min after corticotropin was injected into rats during November to December. No statistically significant differences were found when these experiments were performed during March to September. These differences may be related to the seasonal variation in acute lipolytic responses. 6. These results are discussed in relation to the control of triacylglycerol synthesis and lipoprotein metabolism.

scholarly journals The effects of amphiphilic cationic drugs and inorganic cations on the activity of phosphatidate phosphohydrolase

1977 ◽  
Vol 165 (3) ◽  
pp. 447-454 ◽  
Author(s):  
M Bowley ◽  
J Cooling ◽  
S L Burditt ◽  
D N Brindley
Keyword(s):  
Physical Properties ◽  
Rat Liver ◽  
Partition Coefficients ◽  
Inorganic Cations ◽  
Cationic Drugs ◽  
Phosphatidate Phosphohydrolase ◽  
Glycerolipid Synthesis

1. Phosphatidate phosphohydrolase from the particle-free supernatant of rat liver was assayed by using emulsions of phosphatidate as substrate. 2. The inhibition of the phosphohydrolase by chlorpromazine was of a competitive type with respect to phosphatidate. The potency of various amphiphilic cationic drugs as inhibitors of this reaction was related to their partition coefficients into a phosphatidate emulsion. 3. The effect of chlorpromazine on the phosphohydrolase activity was complementary rather than antagonistic towards Mg2+. Chlorpromazine stimulated the phosphohydrolase activity in the absence of added Mg2+ and was able to replace the requirement for Mg2+. However, at optimum concentrations of Mg2+, chlorpromazine inhibited the reaction, as did Ca2+. The phosphohydrolase activity was also stimulated by Co2+ and to a lesser extent by Mn2+, Fe2+, Fe3+, Ca2+, spermine and spermidine when Mg2+ was not added to the assays. 4. It is concluded that the inhibition of phosphatidate phosphohydrolase by amphiphilic cations can largely be explained by the interaction of these compounds with phosphatidate, which changes the physical properties of the lipid, making it less available for conversion into diacylglycerol. 5. The implications of these results to the effects of amphiphilic cations in redirecting glycerolipid synthesis at the level of phosphatidate are discussed.

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