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Biomedical subjects

T G Redgrave

Publications and source records attributed to T G Redgrave.

At least 91 records · Page 5Linked to original sources
PubMed1984

Hyperlipidemia in tumor-bearing rats.

Hyperlipidemia occurs in animals bearing tumors but the mechanism of its development is uncertain. We have measured triacylglycerol clearance and production rate in rats bearing a transplantable sarcoma. The plasma content of very-low-density lipoprotein triacylglycerol was increased in these tumor-bearing rats but our data excluded a primary clearance defect because the rate of triacylglycerol accumulation (mg/min) after Triton injection was equal to or greater than in normal control rats, except in cachectic rats with very large tumors. The fractional clearance of injected radioactive triacylglycerols was less in tumor-bearing rats than in controls, but the turnover (mg/min) was probably not decreased in the tumor-bearing rats because of their expanded plasma pool. Also inconsistent with a decreased turnover was our finding of a greater production of radioactive plasma triacylglycerols after injection of a tracer dose of radioactive free fatty acid, and unchanged production in Triton-treated rats. Therefore, in the fasted state, the hyperlipidemia of the tumor-bearing rats was associated with an unchanged or possibly an increased flux of hepatic triacylglycerols and a primary clearance defect was excluded. After fat-feeding, rats with tumors developed a higher post-prandial hyperlipidemia than control rats. Therefore, the clearance mechanism for the plasma triacylglycerols was close to saturation in the fasted state, and the added influx of exogenous triacylglycerols was removed less efficiently in the tumor-bearing rats.

Animals↗
PubMed1984

Intolerance to administered lipids in tumor-bearing animals.

Cancer cachexia is a poorly understood phenomenon that contributes to patient intolerance of operations, radiation, and chemotherapy. Reversal of this dysmetabolic state has been attempted by administration of carbohydrates, proteins, and lipids, with little demonstrated clinical benefit. Identification of elevated serum triglycerides (TG) in two tumor-bearing (TB) animal models and recently reported in humans with cancer may be a part of this dysfunctional state. Because lipids makeup energy repletion in patients receiving TPN, the question of how exogenous lipids affect these TB animals needed to be resolved. Intralipid administered by intravenous or gastrointestinal routes raised serum levels in TB animals to greater than 600 mg/dl, even when their baseline TG levels were comparable to nontumor-bearing control animals. The addition of glucose concomitantly with Intralipid failed to prevent TG levels from rising abruptly. Increased lipolytic activity in TB sera was demonstrated and that was not due solely to hypoglycemia or hypoinsulinemia. Administration of lipids to TB animals results in excessively high serum TG levels that appear to be due, in part, to the demonstrated lipolytic activity in TB animal sera.

Animals↗
PubMed1983

Cholesterol content of red blood cells and low-density lipoproteins in hypertriglyceridemia.

The red blood cells and the low-density lipoproteins in hypertriglyceridemia have a lower ratio of unesterified cholesterol to phospholipid than normal. The low-density lipoproteins are also smaller and more dense in hypertriglyceridemia, and contain only 45% of the normal unesterified cholesterol mass. The phase behavior of the lipids shows that normal red cells and low-density lipoproteins are close to saturation with cholesterol, whereas in hypertriglyceridemia less cholesterol is present. Because newly secreted triacylglycerol-rich lipoproteins are poor in cholesterol, their excess production and transport in hypertriglyceridemia may prevent maintenance of the normal cholesterol content of blood cells and low-density lipoproteins. Partitioning of cholesterol into triacylglycerol-rich lipoproteins is able to account for significant fluxes of unesterified cholesterol in the plasma compartment.

Cholesterol↗
PubMed1982

Chylomicron catabolism differs between Hooded and albino laboratory rats.

To extend previous reports that some aspects of lipid metabolism are different between Hooded and albino strains of laboratory rats, thoracic duct lymph chylomicrons were collected and their composition and metabolism were compared in this study. Chylomicrons from Hooded rats had more core components and fewer surface components than albino rats. After adding 1% cholesterol to the diet the ratio of cholesterol:phospholipid was higher in Hooded rat chylomicrons. Nascent lymph chylomicrons from Hooded rats contained less apolipoprotein A-IV, but after incubation with serum there was a gain of apolipoprotein A-IV and a loss of A-I from both types of chylomicron. The ratio of apoC to apoE was higher in Hooded than in albino rats. The metabolism of injected chylomicrons was slower in Hooded rats. Twenty minutes after a single injection, only 1-3% of chylomicron triacylglycerol and 8-13% of chylomicron cholesteryl ester remained in the plasma of albino rats, compared with 6-12% of triacylglycerol and 30-33% of cholesteryl ester in Hooded rats. At 30 min in the Hooded rats, the uptake of injected chylomicron cholesterol into the liver was decreased whereas uptake into other tissues, notably adipose tissue and muscle, was increased. During the steady intravenous injection of chylomicrons from the same strain, the fractional clearance rate of chylomicron triaclyglycerol was about three-fold faster in albino rats than in Hooded rats, and the fractional clearance rate of chylomicron cholesteryl ester was 70% faster in albino rats. When chylomicrons were allowed to circulate for 30 min after injection into functionally hepatectomized rats, with or without heparin, the remnant formation and chemical composition were similar in Hooded and albino rats. Hence the deficiency in chylomicron metabolism in Hooded rats was not due to an absolute impairment in the formation of remnants by the action of lipoprotein lipase in peripheral tissues, although our findings were most likely accounted for by some relative impairment of remnant formation in the Hooded strain. The deficiency in chylomicron metabolism correlated with an increased cholesterolemic response in Hooded rats compared with albino rats when 1% cholesterol was added to the diet.-Jeffery, F., and T. G. Redgrave. Chylomicron catabolism differs between Hooded and albino laboratory rats.

Animals↗
PubMed1982

Specific, saturable binding and uptake of rat chylomicron remnants by rat skin fibroblasts.

To investigate the possible contribution of chylomicron remnants to the accumulation of cholesterol in non-hepatic tissues, rat chylomicron remnants were incubated with rat skin fibroblasts. The binding of remnants was saturable and specific. Native, undegraded chylomicrons were almost as effective as unlabeled remnants in displacing the uptake of labeled remnants. Rat low density and high density lipoproteins were relatively ineffective in displacing the uptake of labeled remnants. Accumulation of radioactive unesterified fatty acids occurred in proportion to the uptake of labeled remnants, indicating probable internalization and degradation of the particles after binding. The incorporation of added [14C]acetate into cell non-saponifiable lipids was not significantly suppressed by added remnants, indicating an apparent lack of feedback regulation of cholesterol biosynthesis after remnant uptake. Our results show that the physiological mechanism underlying uptake of remnants by hepatic parenchymal cells might not be accounted for by tissue or cellular specificity, but may perhaps arise because of the lower capillary permeability of extra-hepatic sites compared with the hepatic sinusoid.

Animals↗
PubMed1981

The content of apolipoprotein B in chylomicron particles.

The number of particles and the mass of apoprotein B were measured in samples of rat lymph chylomicrons in order to assign the mass of apoprotein B per particle. Chylomicron numbers were estimated by electron microscopy after negative staining with 2% potassium phosphotungstate at pH 4.8. The distribution of particle numbers was plotted against particle volume. An exponential relationship was found. Integration of the function gave an estimate of the total number of particles for the total chylomicron volume, which was calculated from the chemical composition and the partial specific volumes of the constituents. Apoprotein B was measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two procedures were employed to allow for the influence of artefactual flattening of the chylomicrons on the electron microscope grid. First, it was reasoned that the flattening artefact would be greatest for the largest particles, so measurements of subfractions of smaller chylomicrons would be less affected by flattening. The mass of apoprotein B per particle was 0.48 x 10(6) daltons in the smallest subfraction. Second, a correction was applied such that the apparent volume of the oblate spheroid produced by flattening was converted to the true volume of the native spherical particle. The flattening artefact increased exponentially with particle size and was an inverse power function of the surface tension. At an assumed value of chylomicron surface tension of 2 mN/m, the apoprotein B per particle was 0.47 x 10(6) daltons.

Animals↗
PubMed1979

Quantitation of the transfer of surface phospholipid of chylomicrons to the high density lipoprotein fraction during the catabolism of chylomicrons in the rat.

Small chylomicrons (CM) labeled with cholesterol, cholesterol ester, phospholipid, and, in some cases, protein, were used to study the fate of these constituents as the CM are catabolized in the circulations of the hepatectomized and intact rat. In the hepatectomized animal after (1/2) h, CM are greatly reduced in volume, surface area, and diameter. During this period, the CM lost >92% of the mass of their triacylglycerol, >77% of the mass of their phospholipid, and >39% of their protein. Compared to the injected CM, the chemically altered particles, called CM "remnants," have a reduction in volume of 96% and in surface area of 88%. The labeled cholesterol esters remain with the CM remnants but, strikingly, a major fraction of the labeled phospholipids and labeled soluble apoproteins leave the CM and are found in the high density lipoprotein (HDL) fraction. The chemical composition of this HDL fraction contains relatively more phospholipid and less cholesterol ester than normal rat HDL. Because of the difference in composition of HDL between normal rats and those given CM, we estimate that the HDL phospholipid pool increased by congruent with25% by the infusion of congruent with 4-5 mg of CM phospholipid. Approximately 5 mg of phospholipid is secreted on CM by a fed rat in 1 h. The findings in hepatectomized rats indicate that a major fraction of the phospholipid and a minor fraction of the protein (soluble non-B apoproteins) of newly secreted CM are transferred from the CM to the HDL fraction during remnant formation. The same process probably occurs in intact rats except that the remnant particles are rapidly removed from the plasma by the liver and a smaller fraction of the surface of the CM enters the HDL fraction.

Animals↗
PubMed1979

Changes in plasma very low density and low density lipoprotein content, composition, and size after a fatty meal in normo- and hypertriglyceridemic man.

Four subfractions of plasma VLDL characterized by decreasing Sf value and LDL were isolated by density gradient preparative ultracentrifugation from normotriglyceridemic (NTG) and hypertriglyceridemic (HTG) (type IV) subjects in the fasting state and after a fatty meal. Chemical analysis and computation of numbers of particles in each fraction showed that the hyperlipidemia of type IV subjects was accounted for by an increase in total numbers of VLDL and a shift in the distribution of VLDL towards particles of larger diameter. Postprandial hyperlipidemia was due to the presence of chylomicron remnants rather than intact chylomicrons, and was accounted for by an increase in particle diameter of the largest VLDL subfraction rather than by an increase in particle numbers. Postprandial hyperlipedemia was accompanied by a shift in the distribution of VLDL towards particles of larger diameter in both NTG and HTG subjects, probably because of competition for the triglyceride-depletion process between chylomicrons and hepatic VLDL. Most chylomicron remnants were removed from the circulation without degradation to smaller VLDL or to LDL, but some remnants were sufficienty small to contribute to smaller VLDL subfractions. The LDL of type IV subjects contained more apoprotein B than those from NTG subjects, and this difference was associated with increases in diameter, molecular weight, density, and the ratio of protein: phospholipid in LDL from type IV subjects. Defective degradation of large VLDL to small VLDL, and of VLDL to LDL may be related to this alteration in apoprotein B content of the lipoproteins in type IV subjects.

Apolipoproteins↗
PubMed1977

Effects of chronic ethanol consumption on the catabolism of chylomicron triacylglycerol and cholesteryl ester in the rat.

Rats were fed for 24 days a liquid diet with ethanol as 36% of calories to produce hyperlipemia and hepatic steatosis. The catabolism of chylomicrons doubly-labeled in the triacylglycerol and cholesteryl ester moieties was studied in conscious rats after ingestion of their usual liquid diets with or without ethanol. A constant intravenous infusion of chylomicrons revealed a defect in chylomicron catabolism after chronic treatment with ethanol. The plasma clearance of chylomicron cholesteryl ester was impaired to a greater extent than clearance of chylomicron triacylglycerol. These findings are consistent with defective catabolism of chylomicron remnants, and suggest that the accumulation of chylomicron remnants in the plasma contributes to the development of increased post-prandial hyperlipemia and chronic hyperlipemia in association with excessive ethanol consumption.

Animals↗
PubMed1977

Clearance of chylomicron triacylglycerol and cholesteryl ester from the plasma of streptozotocin-induced diabetic and hypercholesterolemic hypothyroid rats.

Labeled chylomicrons in thoracic duct lymph were collected after test meals containing 14C cholesterol and 2-3H glyceryl trioleate and were given by intravenous injection to groups of control rats, rats made diabetic by treatment with streptozotocin, and rats made hypothyroid and hypercholesterolemic by a diet containing cholesterol, peanut oil, cholic acid, and thiouracil. In the diabetic rats clearances from the plasma of chylomicron triacylglycerol and cholesteryl ester were impaired. A large variability in triacylglycerol clearance in diabetic rats was ascribed to variability in plasma triacylglycerol concentrations. Adipose tissue lipoprotein lipase activity was not impaired in the female diabetic rats used in this study. In the hypothyroid hypercholesterolemic rats chylomicron cholesteryl ester clearance from the plasma was impaired but chylomicron triacylglycerol was cleared efficiently, and adipose tissue lipoprotein lipase activity was similar to or greater than activity in controls. Ten minutes after intravenous injection most plasma radioactivity was recovered in lipoproteins of density less than 1.006 g/ml in all groups of rats, but relatively more was recovered at this density in both treatment groups. We suggest that chylomicron remnants accumulate in the plasma and contribute to the development of hyperlipemia in both treatment groups, but that the remnants formed in the diabetic rat are less depleted of triacylglycerol than the remnants formed in the hypothyroid hypercholesterolemic rat. It is suggested that factors other than measured lipoprotein lipase activities of adipose tissues may be important in determining the initial extent of hydrolysis of chylomicron triacyglycerol. We propose that the hypercholesterolemic hypothyroid rat is a useful model for the experimental production of the remnants of triacylglycerol-rich primary lipoproteins.

Animals↗
PubMed1977

Catabolism of chylomicron triacylglycerol and cholesteryl ester in genetically obese rats.

The catabolism of chylomicrons was investigated in genetically obese rats and their nonobese littermates, and was compared with catabolism in older Sprague-Dawley rats with body weights similar to the obese rats and their younger controls. Labeled thoracic-duct lymph was collected from donor rats and the catabolism of the labeled chylomicrons was studied after a single intravenous injection or during steady intravenous infusion in unanesthetized, nonfasting, recipient rats. In the genetically obese rats clearances from the plasma of chylomicron triacylglycerol and cholesteryl ester were less than in their nonobese littermates. Fractional clearance rates were reduced for both triacylglycerol and cholesteryl ester but triacylglycerol turnover rate (mg min(-1)) was greater than controls. Chylomicron triacylglycerol clearance was more efficient than cholesteryl ester clearance so that radioactivity remaining in the plasma was relatively depleted in triacylglycerol. The large-bodied old Sprague-Dawley rats showed no reduction in clearance of chylomicron radioactivity in comparison with younger controls. These results suggest that hyperlipidemia in genetically obese rats may be due in part to an accumulation of chylomicron remnants in the plasma. Flotation characteristics of plasma lipoproteins in the obese rats were consistent with this interpretation. However, separate experiments showed that genetically obese, fasting rats also accumulated more triacylglycerol in the plasma after injection of Triton WR 1339. The enlarged plasma triacylglycerol pool appears to derive from a mixture of hepatic and intestinal triacylglycerol-rich lipoproteins which, together, overload their common removal mechanism. Addition of cholesterol to the diets of the obese rats exacerbated their hyperlipemia and hepatic steatosis whereas their nonobese littermates and the large-bodied Sprague-Dawley rats were unaffected.

Aging↗
PubMed1976

Chylomicron metabolism in rabbits fed diets with or without added cholesterol.

Intestinal lymph chylomicrons, isotopically labelled with radioactive triacylglycerol and cholesterol, were injected into normally fed and cholesterol-fed rabbits in order to establish the pattern of clearance of intestinal lipoproteins from the plasma. In normal rabbits the cholesterol moiety of chylomicrons was removed from the plasma less readily than triacylglycerol. In cholesterol-fed rabbits, the clearance of triacylglycerol was unaltered, but clearance of chylomicron cholesterol was further retarded. The majority of the injected lymph cholesterol was recovered in d less than 1.019 g/ml lipoproteins. These observations support the notions that clearance of chylomicron remnants is impaired in the rabbit, and that hypercholesterolaemia in the cholesterol-fed rabbit is due to an accumulation of chylomicron remnants in the plasma.

Animals↗
PubMed1976

Hepatic vitamin A fat-storage cells and the metabolism of chylomicron cholesterol.

These experiments were designed to test the hypothesis that the vitamin A fat-storage cell removes chylomicron remnant cholesterol from hepatic portal venous blood; A modified Ficoll density gradient ultracentrifugation procedure was used to isolate from rat liver cellular fractions that were enriched in vitamin A. In rats fed a normal diet and in rats fed excess vitamin A isolated hepatocytes were fractionated 15 min after the intravenous injection of chylomicrons labelled in vivo with radioactive cholesterol. The results showed that cholesterol radioactivity was not concentrated in the vitamin A enriched cellular fractions, so it was concluded that the vitamin A fat-storage cell is not implicated in clearance of chylomicron remnants by the liver.

Animals↗