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Biomedical subjects

C J Packard

Publications and source records attributed to C J Packard.

At least 199 records · Page 11Linked to original sources
PubMed1982

Receptor-mediated catabolism and tissue uptake of human low density lipoprotein in the cholesterol-fed, atherosclerotic rabbit.

The LDL receptor pathway, which was delineated in cultured cells, is now known to operate in vivo. In this study we have measured the plasma clearances and tissue uptakes of native and chemically modified (1,2-cyclohexanedione-treated or reductively methylated) LDL in rabbits in order to determine the response of the pathway to a high-cholesterol diet. 1 week on the diet increased circulating LDL and suppressed its receptor-mediated plasma clearance and uptake into all tissues. The fractional catabolic rate of the lipoprotein via the receptor-independent route also fell. Continuation of the feeding program for 12 weeks accentuated these changes and virtually eliminated receptor uptake into all tissues so that the plasma decay curves of native and cyclohexanedione-treated LDL were superimposable. Lipoprotein assimilation by the aorta, however, did not follow this general trend. This tissue, after 12 weeks, was variably infiltrated by atheromatous deposits and the appearance of these lesions was associated with a substantial increase in the relative uptakes of both native and chemically modified (cyclohexanedione-treated and reductively methylated) LDL. We concluded (a) that expansion of tissue cholesterol pools virtually abolishes LDL receptor activity in rabbits; and (b) that LDL assimilation (both apparently receptor-mediated and receptor-independent) paradoxically increases at sites where the aorta is affected by atheromatous lesions.

Animals↗
PubMed1982

The reticuloendothelial system and low density lipoprotein metabolism in the rabbit.

This study examines the role of the reticuloendothelial system in the metabolism and tissue uptake of chemically modified human low density lipoprotein (LDL) in rabbits. Treatment with 1,2-cyclohexanedione or HCHO/NaBH4 abolishes receptor-mediated catabolism of the lipoprotein and restricts its clearance to receptor-independent pathways. When the plasma clearances of the two modified lipoproteins were measured in rabbits the 1,2-cyclohexanedione-treated LDL was removed 19% faster (P less than 0.001) than HCHO/NaBH4-treated LDL. This was associated with an increased uptake of 1,2-cyclohexanedione-treated LDL over HCHO/NaBH4-treated LDL into tissues, particularly the liver and spleen, suggesting that their differential clearance may have involved the reticuloendothelial system. To examine this possibility the experiment was repeated in animals whose reticuloendothelial activity had been suppressed by injections of an ethyl oleate emulsion. This reduced the difference in the plasma clearance rates of 1,2-cyclohexanedione-treated LDL and HCHO/NaBH4-treated LDL and virtually abolished their differential tissue uptakes, adding weight to the proposal that the reticuloendothelial system may be involved in the receptor-independent catabolism of LDL.

Animals↗
PubMed1982

Receptor-independent catabolism of low density lipoprotein. Involvement of the reticuloendothelial system.

In this study we examine the effects of intravenous ethyl oleate emulsions on the metabolism of native and cyclohexanedione-modified human low density lipoprotein in rabbits. Treatment produced a highly significant fall in receptor-independent catabolism as measured by the fractional clearance rate of cyclohexanedione-modified low density lipoprotein. Receptor-dependent catabolism (the difference between the fractional clearance rates of native and cyclohexanedione-modified low density lipoprotein) was variably affected with some animals showing a decrease in receptor activity. These data suggest that the reticuloendothelial system makes a substantial contribution to receptor-independent low density lipoprotein catabolism in the rabbit.

Animals↗
PubMed1982

Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinaemic subjects.

This study examines the effects of bezafibrate (200 mg t.i.d.) on LDL metabolism in 7 type II hyperlipoproteinaemic subjects. Eight weeks of treatment lowered plasma cholesterol and triglyceride by 10% and 30%, respectively (P less than 0.02). These reductions were associated with a fall in circulating VLDL (31%, P less than 0.02) and LDL (11%, P less than 0.05), while HDL cholesterol stayed the same. LDL metabolism changed during therapy. The plasma fractional clearance rate (FCR) of autologous [125I]LDL normalized from a low value of 0.256 +/- 0.048 (mean +/- SD) to 0.298 +/- 0.040 pools/day (P less than 0.001). This was attributable to a 65% increase (P less than 0.01) in receptor-mediated LDL catabolism since the clearance of simultaneously injected 1,2-cyclohexanedione-modified [131I]LDL, which measures the receptor-independent pathway, was unaltered (FCR of [131I]cyclohexanedione/LDL in control phase = 0.194 +/- 0.030 pools/day; during drug treatment = 0.194 +/- 0.024 pools/day). We conclude that bezafibrate lowers plasma LDL in type II hyperlipoproteinaemia by promoting its degradation via high affinity receptors.

Adult↗
PubMed1982

Measurement of receptor-independent lipoprotein catabolism using 1,2 cyclohexanedione-modified low density lipoprotein.

The utility of 1,2 cyclohexanedione-modified low density lipoprotein (CHD-LDL) as a marker for the measurement of receptor independent LDL catabolism has been assessed by examining its metabolic properties in cultured human fibroblasts and in rabbits. Cell culture studies showed that the inhibition of high affinity membrane receptor binding produced by the modification could be partially reversed by prolonged incubation of the CHD-LDL at 37 degrees C. Pre-exposure of the complex to alkaline pH (pH 10.5) prevented this and yielded a product that was apparently stable. Despite its regained ability to bind to the fibroblast receptor, 125I-labeled CHD-LDL incubated at 37 degrees C for 24 hr either in vivo or in vitro was removed from rabbit plasma in the same manner as freshly prepared 131I-labeled CHD-LDL and as 131I-labeled CHD-LDL that had been treated at pH 10.5. However, its plasma clearance was significantly faster than that of reductively methylated LDL. We believe that this may result from differential catabolism of these modified lipoproteins rather than from susceptibility of the CHD-LDL to receptor-directed catabolism.

Animals↗
PubMed1982

The hepatobiliary axis and lipoprotein metabolism: effects of bile acid sequestrants and ileal bypass surgery.

Cholesterol excretion from the body is achieved almost exclusively via the hepatobiliary axis. Disruption of the integrity of this pathway by interruption of the enterohepatic circulation produces profound changes in cholesterol metabolism that affect every body tissue. This is particularly evident in the liver and gut which are the major sources of this sterol in the plasma. Elevated plasma cholesterol levels have been implicated in the pathogenesis of atherosclerosis and, in consequence, strenuous efforts have been made to find appropriate hypocholesterolemic therapy to reduce this risk. Medical or surgical interruption of the enterohepatic circulation is, to date, the most successful means of lowering plasma cholesterol, and in this review we examine the ramifications of such therapy on lipid and lipoprotein metabolism in the liver, gut, and plasma.

Animals↗
PubMed1982

High-density lipoprotein subfractions as measured by differential polyanionic precipitation and rate zonal ultracentrifugation.

Recent interest in the putative protective role of high-density lipoprotein (HDL) and its subfractions against atherosclerosis has highlighted the need for a rapid, simple subfractionation procedure. Here we compared HDL subfractionation by two recently developed polyanionic-precipitation methods with the values obtained by rate zonal ultracentrifugation. A similar result for total HDL cholesterol was obtained by all three methods. However, HDL2 cholesterol as measured by the precipitation procedures was significantly higher than the zonal value, and HDL3 was lower. This reflects the different underlying principles involved in the separations and highlights the need for a clearer understanding of the functional roles of the HDL fractions.

Adult↗
PubMed1981

Effect of saturated and unsaturated fat diets on molecular species of phosphatidylcholine and sphingomyelin of human plasma lipoproteins.

Four healthy 21-23-year-old males with normal lipoprotein patterns and plasma lipid concentrations were subjected voluntarily to two diets of 5 weeks duration each: I, highly saturated fat diet; II, highly polyunsaturated fat diet. The VLDL, LDL and HDL3 fractions were isolated by conventional ultracentrifugation from each subject on the high fat diets and the molecular species of the component phosphatidylcholines and sphingomyelins were identified and quantitated by GC-MS of the t-butyldimethylsilyl ethers of the corresponding diacylglycerols and ceramides. It was shown that the diet markedly and rather evenly affected the molecular species of the phosphatidylcholines of all lipoprotein classes. However, the changes in the corresponding major molecular species were reciprocal in nature and were consistent with a demonstrated relative resistance to alterations in surface fluidity. In contrast, the dietary fat had only a minor effect on the composition of the sphingomyelins, and did not alter the characteristic differential distribution of the molecular species among the low and high density lipoprotein classes. These results, which were free of the uncertainties introduced by analyses of derived fatty acid and which were obtained on samples isolated from the same subjects, clearly demonstrate that a complete equilibration of the molecular species of the phospholipids is not attained amont the plasma lipoprotein classes even in the fasting state. The possible physico-chemical and metabolic basis of these observations is briefly discussed.

Adult↗
PubMed1981

Concentration and distribution of human plasma apolipoprotein E.

(1) A sensitive, specific radioimmunoassay for human apolipoprotein E is described. (2) The method gave a plasma apolipoprotein E concentration of 0.107 +/- 0.051 g/l n = 55) in normal subjects. This value increased significantly (to 0.179 +/- 0.088 g/l) in type II hyperlipoproteinaemia (n = 31, p less than 0.01). Type III subjects formed a distinct group whose mean plasma apolipoprotein E concentration was increased four fold over normal (p less than 0.001). The level in type IV subjects (0.136 +/- 0.056, n = 30) did not differ significantly from the normal value. (3) When plasma was subjected to gel filtration on columns of 6% agarose, apolipoprotein E was located in three regions. Peak I corresponded to very low density lipoproteins, Peak II to the area between very low density and low density lipoproteins and Peak III to the leading edge of the high density lipoprotein fraction. No E protein eluted from the column after high density lipoproteins. (4) In contrast, ultracentrifugation of plasma resulted in up to 40% of apolipoprotein E appearing in the lipoprotein-free (d greater than 1.21 kg/l) fraction. This protein appears to hae been stripped largely from high density lipoprotein during ultracentrifugation. (5) Compositional analysis of very low density, intermediate density and low density lipoproteins isolated by a cumulative flotation procedure showed that the apoE/apoB ratio was the same in the first two species but fell to a very low value in low density lipoproteins.

Apolipoproteins↗
PubMed1980

Effects of cholestyramine on receptor-mediated plasma clearance and tissue uptake of human low density lipoproteins in the rabbit.

This study examines the effects of cholestyramine (2 g/day) on the plasma clearance and tissue uptake of human low density lipoprotein (LDL) in rabbits. 1,2-Cyclohexanedione modification of human LDL abolishes its recognition by high affinity cell membrane receptors in vitro and delays its plasma clearance in comparison to native LDL. Consequently, the difference between the fractional rates of catabolism of simultaneously injected native and cyclohexanedione-treated LDL is an index of in vivo receptor-mediated clearance of the lipoprotein. When human 125I-LDL and 131I-cyclohexanedione-treated LDL were injected into rabbits, 44% of the lipoprotein was cleared from the plasma by the receptor mechanism. Various tissues were removed from the animals at the end of the turnover study and their relative uptakes of 125I native and 131I-cyclohexanedione-treated LDL were measured. All exhibited receptor activity to some extent, incorporating more native than cyclohexanedione-modified LDL. The greatest receptor activity per g of tissue was found in lymph nodes, spleen, and liver and, in terms of whole organ uptake, the liver played a major role in LDL catabolism. Treatment of the rabbits with cholestyramine lowered the circulating LDL cholesterol level by promoting its clearance (120%, p < 0.001) via the receptor pathway. This was associated with a virtual doubling of receptor-mediated incorporation of the lipoprotein into the liver. These results suggest that the drain which cholestyramine induces in the hepatic cholesterol pool promotes LDL receptor activity in this organ and thereby lowers the level of circulating LDL.

Animals↗
PubMed1980

Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism.

We studied the influence of cholestyramine (24 g per day) on receptor-mediated and receptor-independent low-density-lipoprotein catabolism in five women with heterozygous familial hypercholesterolemia. Cholestyramine lowered the level of circulating low-density-lipoprotein apoprotein by doubling (P less than 0.01) its fractional clearance via the receptor path, but fractional catabolism by the receptor-independent route remained unchanged. Moreover, although the absolute rate of catabolism of the apoprotein was not affected by treatment, the amounts handled by each pathway altered. Catabolism via the physiologically controllable receptor route increased by 71 per cent (P less than 0.05), but there was a 12 per cent drop in clearance by the nonreceptor pathway. These data demonstrate the utility of cholestyramine in promoting low-density-lipoprotein catabolism via its specific physiologic clearance pathway. They also show that heterozygotes with familial hypercholesterolemia can increase the activity of their low-density-lipoprotein receptors when presented with an appropriate stimulus.

Adult↗
PubMed1980

The relationship between the cholesterol content and subfraction distribution of plasma high-density lipoproteins.

High density lipoprotein subfractions (HDL2 and HDL3) were separated from the plasma of 25 healthy volunteers (13 males, 12 females) rate zonal ultracentrifugation. The rotor elution profile, measured at 280 nm, was used with the specific extinction coefficient for each subfraction (HDL2, 0.60 +/- 0.11 mg protein/A280nm, HDL3, 0.86 +/- 0.10 mg protein/A280nm (n=25) to calculate their plasma concentration. Their protein and lipid composition were also determined by chemical analysis. Plasma lipids, lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein A-II and apolipoprotein B levels were measured in the same subjects and correlated with the HDL subfraction concentrations. HDL cholesterol and apolipoprotein A-I concentrations correlated significantly (p less than 0.01 and 0.02 respectively) with plasma HDL2, but not with HDL3. Indeed, the significantly higher levels of HDL cholesterol and apolipoprotein A-I in the female group could be attributed entirely to an increase in circulating HDL2. This data supports the proposal that the latter subfraction is the major contributor to the anti-atherogenic role of plasma HDL.

Adult↗