[Uptake and degradation of lipoproteins in cells].
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Cholesterol↗
Biomedical subjects
C A Drevon
Publications and source records attributed to C A Drevon.
[New aspects on the relation between plasma lipoproteins and development of atherosclerosis].
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Arteriosclerosis↗
Cholesteryl ester metabolism in fat- and cholesterol/fat-fed guinea pigs.
Guinea pigs were fed a semisynthetic diet containing 10% (by weight) cottonseed oil with or without 1% cholesterol. In response to cholesterol/fat feeding there was a significant accumulation of cholesteryl ester (CE), particularly in the liver, but also in the kidney, spleen and suprarenal glands. The hepatic acyl-CoA:cholesterol acyltransferase (ACAT) increased 5-10 times when the animals were fed cholesterol fat during 11 weeks while the acid cholesterol esterase (CE-ase) was similar in the two dietary groups. Intestinal lymph showed the highest content of cholesterol (both free and esterified) in guinea pigs fed cholesterol/fat. A low activity of lecithin:cholesterol acyltransferase (LCAT) was present in the intestinal lymph, irrespective of dietary composition. Triglyceride-rich lipoproteins seem to inhibit LCAT activity in the intestinal lymph. Plasma cholesterol levels in animals fed cholesterol/fat increased markedly while LCAT remained unaffected by the diets. Activity of ACAT and CE-ase in kidney and spleen was low compared to liver tissue and the enzyme activities were not affected by the cholesterol/fat feeding.
Adrenal Glands↗
Properties and subcellular distribution of acyl-CoA: cholesterol acyltransferase (ACAT) in guinea-pig liver.
The optimal in vivo conditions for measuring liver acyl-CoA:cholesterol acyltransferase, EC.2.2.1.26 (ACAT) activity in cytoplasmic extract from guinea-pigs have been examined. ACAT in liver from ordinarily fed guinea-pigs is very low. The effect of different compounds on ACAT activity was evaluated. Sodium fluoride, oligomycin, divalent cations, oleyl-CoA, and bile acids were all shown to inhibit ACAT activity markedly. Albumin stimulated the cholesterol esterification independently of the presence of fatty acids. Subcellular distribution of liver ACAT in relation to different marker enzymes shows that the bulk of ACAT activity is present in the microsomal fraction. By comparing the esterification of exogenous and endogenous cholesterol, the results indicate that these two substrates are not esterified to the same extent. Both the 'enzyme" level and substrate quality are of importance for the high ACAT activity found in rat-liver homogenates compared to guinea-pig.
Acyl Coenzyme A↗
Uptake and degradation of cholesterol ester-labelled rat plasma lipoproteins in purified rat hepatocytes and nonparenchymal liver cells.
1. A new method for isolation and purification of rat liver hepatocytes and nonparenchymal cells by differential centrifugation is described. 2. Cholesterol ester-labelled lipoproteins (prepared by the action of lecithin: cholesterol acyltransferase) intravenously injected were taken up by hepatocytes and nonparenchymal cells. 3. Hepatocytes and nonparenchymal cells in suspension were able to take up and hydrolyse the cholesterol ester portion of lipoproteins. 4. Uptake of cholesterol ester labelled whole rat plasma and high density lipoproteins (HDL) increased with increasing concentrations until a distinct saturation level was reached in hepatocytes. In nonparenchymal cells there was no saturation of lipoprotein uptake. 5. Concanavalin A inhibited cholesterol ester-labelled lipoprotein uptake in hepatocytes, indicating that the uptake at least partially depends on carbohydrate sites on the cell surface. The uptake in nonparenchymal cells was unaffected of concanavalin A. 6. The specific activity of the acid cholesterol ester hydrolase was the same in homogenates from hepatocytes and nonparenchymal cells while acyl-CoA: cholesterol acyltransferase was found almost exclusively in hepatocytes.
Acid Phosphatase↗
The effects of cholesterol/fat feeding on lipid levels and morphological structures in liver, kidney and spleen in guinea pigs.
Guinea pigs were fed a semisynthetic diet containing 10 per cent (by weight) cottonseed oil with or without 1 per cent cholesterol. In the animals fed fat, the lipid levels and the morphology remained normal in all tissues studied. Concomitantly with a marked accumulation of cholesteryl ester (CE) in the liver, however, many microscopical changes occurred in guinea pigs fed cholesterol/fat. A prominent deposition of lipids in vacuoles, mostly without delimitating membranes, where observed at centrilobular sites. Multivacuolated, secondary lysosomes, membrane bound lipid vacuoles (lipolysosomes) and myelin figures were found both in hepatocytes and Kupffer cells. Myelin figures and crystalline clefts were observed more often in Kupffer cells than in hepatocytes. The granular endoplasmic reticulum in the Kupffer cells was grossly dilated and filled with an amorphous material. Both the biochemical and the morphological findings in hepatocytes and Kupffer cells are very similar to those observed in cholesteryl ester storage disease and in Wolman's disease. These two lipid storage diseases are both related to deficiency of an acid lipase in the liver. Measurement of the acid liver CE hydrolase in guinea pigs fed fat and in those fed cholesterol/fat showed similar activity. A relative deficiency of this enzyme activity could be the reason for the development of the enormous CE storage in guinea pig livers. These findings suggest that guinea pigs fed cholesterol/fat, in some respects, can be used as a model for Wolman's disease and cholesteryl ester storage disease. We did not find any microscopical changes in the kidneys from animals fed cholesterol/fat, thus indicating that the experimental condition it not useful as a model for studies of the kidney changes in lecithin:cholesterol acyltransferase (LCAT) deficiency.
Animals↗
Coenzyme-A-dependent esterification of cholesterol in intestinal mucosa from guinea-pig. Influence of diet on the enzyme activity.
Guinea-pig intestinal mucosa contains a microsomal enzyme which catalyses the esterification of cholesterol. The enzyme is CoA-dependent and probably an acyl-CoA-cholesterol acyltransferase (ACAT) (E.C. 2.3.1.26). The apparent Km for the CoA in the combined enzyme reaction is 3.3 x 10(-5)M. The specific activity of cholesterol esterification is about five times higher in young suckling animals than in ordinary fed adult animals. Feeding fat and fat/cholesterol diets increases the activity two- to five-fold. Concomitantly the fat/cholesterol fed animals get a marked accumulation of free and esterified cholesterol in mucosal cells.
Acyltransferases↗
Cholesterol esterification and lipids in plasma and liver from newborn and young guinea pigs raised on milk and non-milk diet.
Plasma lecithin:cholesterol acyltransfer (LCAT), liver acyl-CoA:cholesterol acyltransfer (ACAT) and plasma and liver lipids were examined in newborn and young guinea pigs fed ordinary or a non-milk diet. LCAT in newborns was about 70% of the adult value, increased the first 3 days to values about three times the adult value, and decreased during the next 3 weeks to about adult value. Plasma lipids varied in a similar way. Liver ACAT in newborns was considerably higher than in adults. In young animals on non-milk diet the LCAT and ACAT were lower than in normally fed animals. LCAT was positively correlated to free cholesterol in plasma.
Acyltransferases↗
Effect of lipid emulsions on the plasma lecithin: cholesterol acyltransfer in guinea pigs.
Addition of triglyceride/phospholipid emulsion to adult guinea pig plasma more than doubled the cholesteryl ester (CE) production. Plasma from newborn guinea pigs was stimulated to a lower degree. The increase in CE production was dependant on the type and amount of phospholipids in the lipid emulsions. Egg phospholipids stimulated the cholesterol esterification while partially hydrogenated soy phospholipids (with high content of saturated fatty acids) inhibited the reaction. The stimulation of CE formation was probably due to transfer of phosphatidyl choline (PC) from the emulsion to the high density lipoproteins since the stimulation was: (a) dependant on a preincubation time, (b) less pronounced in newborn animals with high plasma PC levels, and (c) detected in plasma fractions from which the lipid emulsion had been removed.
Acyltransferases↗
Interaction of ethanol with codeine metabolism in rat hepatocytes: a multicompartmental model.
A multicompartmental pharmacokinetic model is presented, which based upon data from a previous study, describes the effects of ethanol (60 mM) on the metabolism of codeine (10 microM) in isolated rat hepatocytes. According to this model, about one third of codeine metabolized was transformed to morphine (13%) and norcodeine (18%), and two-thirds to unknown metabolites in the absence of ethanol. In the presence of ethanol, the apparent first order fractional rate of total codeine metabolism was reduced by 66% (0.0783 vs 0.0271 min-1). There was no alteration in the portion of codeine metabolized to norcodeine, but there was a 44% decrease in the fraction transformed to unknown metabolites and a tripling in the portion transformed to morphine. The fractional rate of codeine O-demethylation to morphine was apparently not sensitive to ethanol. In the absence of ethanol, about two-thirds of morphine was metabolized to morphine-3-glucuronide and the other third to unidentified metabolites. Only the glucuronidation process seemed to be inhibited by ethanol. The fractional rate of further metabolism of norcodeine to normorphine was similar in the absence or presence of ethanol. In conclusion ethanol co-incubation with codeine resulted in an inhibition of codeine conversion to unknown metabolites and norcodeine, and with morphine to morphine-3-glucuronide, but no inhibition in morphine production.
Animals↗