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C Lutton

Publications and source records attributed to C Lutton.

At least 19 recordsLinked to original sources
PubMed1992

Metabolism of intestinal triglyceride-rich lipoproteins in the genetically hypercholesterolemic rat (RICO)

Experiments were carried out to compare the catabolism of intestinal lipoproteins between genetically hypercholesterolemic (RICO) and normocholesterolemic (SW) rats. Kinetics of plasma cholesteryl ester were studied after injection of cholesterol-labeled chylomicrons or VLDL. The chylomicron clearance is reduced in the RICO rat (rate constant, K = 7.2 +/- 0.1 h-1 vs. 10.7 +/- 0.1 h-1 in SW rat), while a much more minor alteration was observed in the catabolism of lymph VLDL (K = 4.3 +/- 0.6 h-1 in the RICO rat vs. 5.1 +/- 0.4 h-1). The injection of chylomicrons from SW rats to RICO rats and from RICO rats to SW rats showed that the fall in the rate of catabolism of chylomicrons in RICO rats was not secondary to an increase in the production rate, but was related to the lipoprotein particle itself without any alteration of the catabolic system. The reduction in the rate of catabolism of chylomicrons in the RICO rat could be related to a change in their apolipoprotein composition (increase in the proportion of apolipoprotein E = 12 +/- 2% vs. 3 +/- 1% in the SW rat).

Animals↗
PubMed1992

Overestimation of the lipoprotein fractional catabolic rate (FCR) measured in short duration experiments.

The aim of the study was to compare two methods classically used in rats to determine the fractional catabolic rate (FCR) of labeled high or low density lipoproteins: constant infusion and single pulse. The FC of [14C]-sucrose HDL (High density lipoprotein) was studied. For the short term experiment (8 hours), both methods gave similar FCR determined 8 hours after HDL constant infusion (9.4%.h-1 +/- 0.6) or single pulse (8.5%.h-1 +/- 0.4), values significantly higher than those measured 24 hr after the single pulse (6.2%.h-1 +/- 0.3). The identification and simulation of the model representing HDL movements between an intravascular and extravascular pool, after single pulse and constant infusion methods, demonstrated that FCR of lipoproteins cannot be precisely measured with techniques involving excessively short observation periods.

Animals↗
PubMed1992

[Metabolism of plasma cholesterol and lipoproteins after total resection of the small intestine in patients with parenteral nutrition. Effects of the amount of phospholipids infused].

The aim of this study was to investigate the plasma lipoprotein profile in 2 patients treated by parenteral nutrition for total small bowel resection over a 15 month period. According to the amount of infused phospholipids (6 g/d vs 3 g/d), infused during 4 non consecutive 6 month or 6 week periods, HDL-cholesterol, apolipoproteins AI and B plasma levels were 30 to 50% below normal values. During the higher phospholipid supply, cholesterolemia seemed normal; each phospholipid supply decrease was followed by a reduction of cholesterol, phospholipids and apolipoprotein B plasma levels of 40, 50 and 25%, respectively, while HDL-cholesterol and apolipoprotein AI plasma levels remained unchanged. Density gradient ultracentrifugation showed that plasma cholesterol changes were mainly due to cholesterol changes (as free cholesterol associated with phospholipids) located in the density range of 1.019-1.040, reflecting the presence of lipoprotein X-like particles, whose levels remained unchanged during each period. An apolipoprotein E, CII and CIII enrichment of plasma was observed and was more pronounced when patients received higher phospholipid infusion. These results show that, in patients without a small bowel, minor changes in phospholipids supply are responsible for serious alterations of the lipoprotein profile; formation of lipoprotein X-like particles could be favored by the low HDL levels in these patients.

Apolipoproteins↗
PubMed1991

In vivo effect of simvastatin on lipoprotein cholesteryl ester metabolism in normocholesterolemic volunteers.

A kinetic study on lipoprotein cholesteryl ester metabolism was carried out in 4 normolipidemic volunteers before and after treatment with simvastatin. They received LDL labelled with 3H-cholesteryl linoleate. A lipoprotein cholesteryl ester model was developed that fit the radioactivity in LDL, HDL and VLDL cholesteryl ester during 24 hours following injection. Before treatment, the model is consistent with previously reported data. Moreover our results suggest that, in normal fasting subjects, the efflux of plasma cholesteryl ester is almost exclusively derived from LDL. Administration of drug decreased LDL cholesteryl ester concentration by 35%. After treatment, the rate constant concerning LDL catabolism was increased by 25% and the model required the existence of a direct removal of VLDL cholesteryl ester (40% of total VLDL turnover). Our results suggest that the reduction in the LDL cholesteryl ester concentration induced by treatment with simvastatin is due to an increase in the uptake of LDL and LDL precursors (VLDL, VLDL remnants) by LDL receptors.

Adult↗
PubMed1991

Dietary cholesterol, membrane cholesterol and cholesterol synthesis.

After describing the main steps of cholesterol biosynthesis the author recalls that the cholesterogenesis rate is feedback-inhibited by dietary cholesterol and examines the various processes of modulation. Hydroxy-3-methylglutaryl (HMG) CoA reductase, the key rate-limiting enzyme, is a 97 kDa endoplasmic reticulum glycoprotein, anchored 7-fold in this membrane. The N-terminal membrane-bound domain plays a fundamental role in the modulation of reductase activity. This modulation is essentially mediated by decreased gene transcription and enhanced degradation of the protein. The possible modulation by a bicyclic cascade system involving phosphorylation (inactivation) and dephosphorylation (activation) of reductase does not seem to play an essential role in vivo. Finally, recent data show that the lipid composition (C/P molar ratio) of some reticular membranes (fibroblasts, for example) can strongly modulate the activity of this ubiquitous enzyme.

Animals↗
PubMed1991

Biodynamics of cholesterol and bile acids in the lithiasic hamster.

By using the isotopic equilibrium method in the young male Syrian hamster, the rates of cholesterol turnover processes, i.e. dietary cholesterol absorption, cholesterol synthesis, cholesterol excretion in the faeces and urine and cholesterol transformation into bile acids, were determined in the hamster receiving a control (C) or a lithogenic diet (L) for 7 weeks. At the end of this period the gall bladder of all animals in group L contained cholesterol gallstones. The coefficient of dietary cholesterol absorption was reduced by 26%, cholesterol synthesis and cholesterol faecal excretion were twofold higher in group L than in group C. Bile acid content in the small intestine was diminished in group L, but bile acid composition was similar in the two groups. The increase in cholesterogenesis in lithiasic animals essentially took place in the liver. Bile acid biosynthesis did not significantly differ in the two groups, but represented only 35% of total cholesterol input (dietary absorption + internal secretion) in group L v. 52% in group C. Thus, in the lithiasic hamster, hepatic synthesis of cholesterol and bile acids are not coupled. The molar percentage of cholesterol in bile was twofold higher in group L than in group C but those of bile acids and of phospholipids were not modified. In the lithiasic hamster the specific activity of biliary cholesterol was similar to that in plasma and liver. Consequently, biliary cholesterol does not derive directly from cholesterol newly synthesized in the liver but from hepatic cholesterol rapidly exchangeable with plasma cholesterol.

Animals↗
PubMed1990

Effects of intravenous infusions of commercial fat emulsions (Intralipid 10 or 20%) on rat plasma lipoproteins: phospholipids in excess are the main precursors of lipoprotein-X-like particles.

Like most commercial parenteral emulsions, Intralipid contains the same amount of phospholipids (12 mg/ml) to stabilize 100 or 200 mg of soybean oil (10 or 20% formula, respectively). By centrifugation, 10 or 20% Intralipid was separated into a supernatant, fat particles containing the bulk of triacylglycerols stabilized by a fraction of phospholipids and an infranatant--called mesophase--consisting mainly of phospholipids used in excess as emulsifier. We observed that the initial triacylglycerol/phospholipid ratio of the emulsion (100/12 and 200/12, respectively) determines the size of the triacylglycerol-rich particles (260 and 350 nm) as well as the phospholipid content of the mesophase (6.02 and 4.67 mg/ml). To understand the mechanism of the lipoprotein-X (LPX) accumulation generally reported after intravenous fat infusions, plasma lipid levels and lipoprotein profiles were first compared in the rats after infusion (at a constant rate of 0.5 or 1 ml/h for 43 h) of Intralipid 10 or 20%. For the same intravenous triacylglycerol load (100 mg/h), rats infused with Intralipid 10% at 1 ml/h displayed higher triacylglycerol levels than rats infused with the 20% emulsion at 0.5 ml/h, suggesting that the size of exogenous fat particles modulated the catabolic rate of their triacylglycerols. The plasma levels of LPX varied according to the infusion rate of phospholipids not associated with triacylglycerol-rich particles of the emulsion. Moreover, an apo E and apo B enrichment of plasma and an elevation of the apo B48/apo B100 ratio was always observed after Intralipid infusions. In order to confirm that phospholipids of the mesophase are the main LPX precursors, lipoprotein profiles were then compared in the rats after intravenous infusion, at a constant rate of 1 ml/h, of either the mesophase or a suspension of triacylglycerol-rich particles isolated from Intralipid 20%. As expected, significant LPX amounts were only detected in rats infused with the pure mesophase of the emulsion. It was concluded that products of the lipolysis of exogenous fat particles play only a minor role in the formation of LPX. In fact these abnormal lipoproteins are generated by phospholipids of the mesophase which, like infused liposomes, actively mobilize endogenous free cholesterol. Consequently, in order to be considered as true chylomicron models for safe fat delivery in parenteral nutrition and in order to prevent some detrimental effects on cholesterol metabolism, commercial emulsions should be cleared of phospholipid excess.

Animals↗
PubMed1990

Lipoprotein lipase and hepatic lipase activities in a hypercholesterolaemic (RICO) strain of rat. Effect of dietary cholesterol.

Hepatic lipase (HL) and lipoprotein lipase (LPL) were assayed in heparinized plasma from male normocholesterolaemic (SW) and genetically hypercholesterolaemic (RICO) rats. Both strains were fed on either a semi-purified control diet or the same diet enriched with 0.5% or 1% cholesterol. HL activity was similar in both groups of rats fed on the control diet. LPL activity was found to be significantly lower in RICO rats (35% decrease, P less than 0.05). Feeding with a high-cholesterol diet led to a decrease in HL activity (15-23%) in both groups of rats but no change was detected in LPL activity, which remained consistently lower in the RICO rats. Thus, with the control diet, LPL activity is lower in RICO rats but presumably is not rate-limiting for their triacylglycerol clearance, given the normal triacylglycerol levels present. After cholesterol feeding, however, the lower LPL activity may become rate-limiting together with the decrease in HL activity, as in these circumstances hypertriacylglycerolaemia was evident and the hypercholesterolaemia of this strain was further increased.

Animals↗
PubMed1990

The mesophase of parenteral fat emulsion is both substrate and inhibitor of lipoprotein lipase and hepatic lipase.

Six 10% and 20% parenteral fat emulsions were separated by centrifugation into two fractions: (1) a supernatant containing the bulk of triacylglycerols (Tg) as fat particles stabilized by phospholipids (PL); and (2) an infranatant, called mesophase, consisting essentially of PL (one third of the original PL in the 10% formula, one sixth in the 20% formula, in the case of emulsions containing 12 g PL.L-1) and small amounts of Tg and free sterols, probably in the form of liposomes. The lipolytic enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL), involved in the Tg-rich lipoprotein clearance, hydrolyze both types of particles, although Tg-fat particles are their preferred substrate. Inactivated serum (providing apo C-II) is needed to ensure the maximum LPL hydrolysis rate of both types of particles. It partially inhibits the HL activity on the mesophase. Substrate of the lipolytic enzymes, the mesophase, is also an inhibitor of their activity, the inhibition being directly proportional to the amount of PL contained in the mesophase. This inhibition is of uncompetitive type. For LPL, it seems that the mesophase acts on a site distinct from that of the apo C-II binding site. These results partly explain the low PL clearance after a fat emulsion infusion. But in particular, they help to explain the lower clearance of a 10% emulsion (larger PL excess) compared with a 20% emulsion (with the same amount of Tg, but less PL excess).

Animals↗
PubMed1990

Metabolism and effects on biliary lipid secretion of murocholic acid in the hamster.

The metabolism of murocholic acid (MC), a 6 beta-hydroxylated bile acid, was investigated after intravenous (i.v.), intraduodenal (i.d.) or intragastric (i.g.) administration to bile fistula hamsters. The effects on biliary cholesterol and phospholipid secretion were measured during intravenous infusions of increasing doses of [3H]MC. At an infusion rate of 0.1 or 1 mumol.min-1.kg-1, the hepatic uptake was effective. More than 90% of the dose was recovered in bile within 4 h. A bolus injection of 500 micrograms of [3H]MC in the duodenum led to a rapid and efficient biliary secretion of radioactivity. Increasing i.v. infused doses of MC had no effect on bile flow or biliary cholesterol output compared to the controls. Phospholipid secretion was significantly reduced (0.113 mumol.min-1.kg-1 versus 0.238 mumol.min-1.kg-1 in in controls per mumol.min-1.kg-1 of excreted bile acids) as MC progressively replaced the endogenous bile acid pool in bile. After i.v. and i.d. administration, MC was secreted in bile as glyco and tauro conjugates without additional hepatic hydroxylation, sulfation or glucuronidation. The i.g. ingestion of MC followed by the faecal analysis of metabolites showed the formation of hyodeoxycholic acid and 3 alpha-OH-6-oxo-5 beta-cholan-24-oic acid. An equivalent experiment with hyodeoxycholic acid gave MC and the same oxo bile acid. We concluded that MC is metabolized by the hamster liver as an endogenous bile acid, which undergoes intestinal bacterial transformation into a 6-oxo derivative and is then reduced into hyodeoxycholic acid. This process is completely reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Critical analysis of the use of 14C-acetate for measuring in vivo rat cholesterol synthesis.

The bulk of cholesterol produced by the liver and the gut enters the mobile pool of body cholesterol. This process is called internal secretion in contrast with the fraction of biosynthesized cholesterol directly eliminated in the feces (fecal external secretion). In rats, under various conditions, a linear relationship was found between the rates of internal secretion measured by the isotope equilibrium method (range: 10-60 mg/day) and the sum of sterol radioactivities measured in liver and intestine 70 min after a [14C]-acetate pulse. In fact, a better correlation was found between the radioactivities of liver sterols and the values for internal secretion. In this new relationship, the ordinate at the origin corresponds to a minimal internal secretion of about 10 mg/day, which implies an important extrahepatic cholesterol production, probably from the gut. Indeed, in adult male rats, fed a semi-purified sucrose-rich diet, the relative contribution of this organ to the internal secretion was higher than in adult rats fed a commercial diet and higher than in young animals, whatever the circadian period. It can be concluded that some of the discrepancies observed in the literature about the relative participation of the intestine and the liver in the internal secretion of cholesterol are probably due to differences in experimental and nutritional conditions (age and sex of the animals, diet composition, time of the circadian cycle) rather than to the cholesterol precursor used (3H2O or [14C] acetate) to assess the activity of cholesterol synthesis. Indeed, a comparative study of 3H2O and [14C]acetate incorporation into sterols of enterocytes indicated the same crypt-villus radioactive gradient, regardless of the intestinal site studied (duodenum, jejunum or ileum) and thus validated the use of [14C]acetate. Other experiments however, showed evidence of some local differences in the cytosolic dilution of labeled acetyl CoA by the endogenous cholesterol precursor in rats under various conditions (control or cholestyramine-enriched diet, parenteral nutrition). After intravenous infusion of 1,2[13C]acetate, mass fragmentography of free cholesterol isolated from liver and intestine indicated different 13C-labeling patterns of newly synthesized molecules. They indicate that cholesterol is generally synthesized from acetyl CoA with a lower 13C-content in the liver than in the intestine. The local endogenous flow of acetyl CoA used for cholesterol synthesis was about 2-fold higher in the hepatocytes than in the enterocytes. This conclusion was confirmed by the results obtained with several experimental groups exhibiting a large range of both internal secretion of cholesterol and sterol radioactivities in liver and intestine after [14C]acetate injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed1990

Turnover of [14C] sucrose HDL and uptake by organs in the normal or genetically hypercholesterolemic (RICO) rat using a constant infusion method.

The turnover and tissular uptake of HDL (d 1.095-1.21) have been compared in normocholesterolemic or genetically hypercholesterolemic rats by a constant infusion method of [14C] sucrose labelled HDL for 8 h. The HDL clearance rate was not significantly smaller in the RICO than in the normocholesterolemic animal (320 +/- 22 microliters.h-1 versus 366 +/- 24 microliters.h-1 per 100 g of rat). It was the same case for the fractional catabolic rate, respectively equal to 7.8 and 9.4 +/- 0.6%.h-1. For both strains, liver and skeletal muscle were the main catabolic sites for HDL. The HDL uptake rates in intestine or kidney were 3-4-fold smaller than those in the liver. In the RICO rat, intestine, testis and adrenals showed a lesser HDL uptake capacity (expressed per g of organ) than the normocholesterolemic rat.

Animals↗
PubMed1990

[Cholesterol and bile acid dynamics: comparative aspects].

While the cholesterol concentration in a given tissue is similar in the rat, pig or man, the relative importance of the processes regulating the input (absorption and synthesis) and output (faecal cholesterol and bile acid excretions) of the cholesterol system is very different from one species to another. The rat, whose cholesterolaemia does not significantly increase after cholesterol addition to the diet ("hyporesponding" animal), successfully adapts its bile acid biosynthesis to variations in cholesterol input. This process accounts for 80 to 85% of cholesterol output, faecal cholesterol excretion being a minor process. The latter results from a low liver cholesterol secretion in the bile due to the low hydrophobicity of its main bile acids. Furthermore, in this animal a high intestinal synthesis of cholesterol and apolipoproteins (particularly B48) is observed. The latter are secreted as very light lipoproteins (chylomicrons and VLDL) with a faster plasma turnover than the VLDL (apoB100, E...) secreted by the liver. The "remnants" of rat VLDL are essentially very rapidly taken up by the liver; their interplasmatic transformation pathway into IDL and LDL is not very significant (less than or equal to 10%). Man, who has a more significant hypercholesterolaemia after exogenous cholesterol ingestion ("hyperresponding" subject) seems to have a less modulable capacity for transforming cholesterol into bile acids. This process accounts for only 50% of cholesterol output, faecal cholesterol excretion being quantitatively just as significant. Cholesterol concentration and the cholesterol/bile acid ratio are much higher in human than in rat bile, the main bile acids being more hydrophobic. While both the intestine and liver contribute to cholesterogenesis, the relative importance of the latter is probably greater in man than in the rat. Moreover, a larger fraction of plasma VLDL is transformed into IDL and LDL, the latter representing the main plasma cholesterol carrier. Determining whether the differences between the biodynamics of cholesterol processes in the rat and in man can be generalised to mammals with low or high sensitivities to hypercholesterolaemia and atherosclerosis seems to be a fundamental research objective for the next few years.

Animals↗
PubMed1988

Effects of chronic glucagon administration on cholesterol and bile acid metabolism.

Male adult Wistar rats received daily, at 9 a.m. and 5 p.m., 10 micrograms of Zn-protamine glucagon for 21 days by subcutaneous injections. The blood glucose level was not significantly modified. Cholesterol and triacylglycerol levels were decreased by 40 and 70% in plasma but not in the liver. The rates of cholesterol turnover processes were determined in vivo with an isotope balance method. Internal secretion of cholesterol (13.8 +/- 0.5 mg/day per rat in control rats and 22.4 +/- 0.9 mg/day per rat in glucagon-treated rats) and cholesterol transformation into bile acids were strikingly increased by chronic administration of glucagon. Biliary secretion rates of bile acids measured by a wash-out method were increased by 139%, while the intestinal bile acid pool was not changed. The enterohepatic cycle number was increased from five per day in control rats to nine per day in glucagon-treated rats. An increased turnover rate of the exchangeable cholesterol would explain the hypocholesterolemic effect of glucagon.

Acetates↗
PubMed1988

Cholesterol metabolism in the genetically hypercholesterolemic (RICO) rat. II. A study of plasma lipoproteins and effect of dietary cholesterol.

The high plasma cholesterol concentration of the genetically hypercholesterolemic RICO rats fed a low cholesterol base diet (1.28 mg/ml) compared to that of SW rats (0.73 mg/ml) results from an increase in the cholesterol content of the d greater than or equal to 1.006 lipoproteins. Since the composition of each type of lipoprotein is similar in the two groups of rats, the RICO rat, therefore, is hyperlipoproteinemic with an increase in the number of lipoprotein particles, except VLDL and chylomicrons. Furthermore, the apolipoprotein E (apoE) content in the d less than or equal to 1.063 lipoproteins is higher in RICO than in SW rats, while that of apoA-I in HDL is lower. In rats fed 0.5% cholesterol base diet, cholesterolemia doubles in the two groups (SWCH, 1.32 +/- 0.10 mg/ml; RICOCH, 2.10 +/- 0.09 mg/ml). This hypercholesterolemia is due to an increased cholesterol content in VLDL and chylomicrons. These lipoproteins carry 60% (in SWCH) and 45% (in RICOCH) of the plasma cholesterol and are cholesterol-enriched compared with the lipoproteins observed in rats fed the base diet. In RICOCH, 24% of the plasma cholesterol is found in apoE-rich LDL2 (1.040 less than or equal to d less than or equal to 1.063), whereas in SWCH, this fraction contains only 11% of the plasma cholesterol. Finally, as before with the base diet, RICOCH shows an apoE enrichment of the d less than or equal to 1.063 lipoproteins and an apoA-I depletion of HDL compared to SWCH. These data suggest that hypercholesterolemia of the RICO rats results from a modification in the turnover of apoE-containing lipoproteins.

Animals↗
PubMed1988

Induction of long-lasting hypercholesterolemia in the rat fed a cystine-enriched diet.

The influence of dietary excess (5%) of L-cystine on rat plasma lipoproteins was examined. After only one week of cystine feeding, an increase in the plasma cholesterol level and a decrease in triglyceride levels were observed. The increase in cholesterol level became greater when the duration of cystine-enriched diet increased until eight weeks (+131% after eight weeks), but no further increase occurred between 8 and 20 weeks. This change was essentially due to the progressive increase in cholesterol levels in high density lipoproteins (HDL) and in lipoproteins isolated between 1.040 and 1.063 g/ml, i.e., certain low density lipoproteins (LDL2), and containing mainly apoE-rich lipoproteins (HDL1). The decrease in plasma triglycerides resulted from that of chylomicrons and very low density lipoproteins (VLDL). The effects observed after four or eight weeks of cystine feeding were maintained for eight weeks after replacing the cystine diet by the standard diet. Ingestion of the standard diet containing either cholestyramine (2%) or probucol (0.25%) following eight weeks of cystine feeding significantly decreased plasma cholesterol levels. It is concluded that cystine-fed rats are a useful tool of investigation for understanding mechanisms leading to increased plasma cholesterol level and for hypocholesterolemic drug trials.

Animals↗