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Biomedical subjects

C J Packard

Publications and source records attributed to C J Packard.

At least 217 records · Page 12Linked to original sources
PubMed1980

Combined drug therapy for familial hypercholesterolemia.

Six familial hypercholesterolemic subjects were treated with a combination of cholestyramine (16 g/day) and nicotinic acid (3 g/day). This therapy consistently lowered plasma cholesterol and triglyceride by, on average, 41% and 37% respectively. Very low density and low density lipoprotein cholesterol fell, while high density lipoprotein cholesterol rose significantly. Plasma apolipoprotein levels were also affected by treatment. Apolipoprotein A-I rose 26% and apolipoprotein B fell 31%. In addition, there was a fourfold increase in plasma high density lipoprotein subfraction2 (HDL2), although HDL3 remained unaltered. These favorable changes in a number of atherosclerotic risk indices commend the use of this drug combination in the treatment of heterozygous familial hypercholesterolemia.

Adult↗
PubMed1980

Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man.

This study examined the effects of dietary saturated and polyunsaturated fat on the chemical composition and metabolism of low density lipoproteins (LDL) in eight normal male subjects. The influence of these diets on fecal sterol excretion was also measured in four of the subjects. When compared with the saturated fat diet, the polyunsaturated diet lowered both plasma cholesterol polyunsaturated diet lowered both plasma cholesterol (23%, P less than 0.001) and triglyceride (14%, P less than 0.001) levels. Sixty-seven percent of the reduction in the former lipid resulted from a fall in LDL cholesterol (23%, P less than 0.001), although very low density (VLDL) and high density lipoprotein (HDL) cholesterol levels also fell (by 27% and 20% of their respective control value). These changes were accompanied by significant alterations in LDL composition. Specifically, during polyunsaturated fat feeding, the relative percentage cholesterol in the LDL fraction fell while that of phospholipid rose. There was no change in the percentage protein or triglyceride. The fatty acid components of LDL triglyceride, cholesteryl esters, and phospholipid were also affected by dietary fat saturation level. Overall, polyunsaturated fat feeding produced an enrichment in linoleate with reciprocal changes in palmitate, stearate, and oleate which affected triglycerides more than cholesteryl esters and phospholipids. The above changes in LDL composition were associated with alterations in the metabolism of LDL apoprotein (apoLDL). The polyunsaturated deit lowered plasma apoLDL by 13% (P less than 0.05). This resulted from an increase in the fractional catabolic rate of LDL (whether determined by plasma decay curve analysis (P less than 0.05) or urine/plasma radioactivity ratios (P less than 0.001) without significant alteration of its corporeal distribution or synthetic rate. The polyunsaturated fat diet did not cause a consistent change in fecal neutral or acidic steroid excretion. We conclude that the hypocholesterolemic action of polyunsaturated fat diets is effected by multiple mechanisms whose expression may vary from patient to patient.

Adult↗
PubMed1979

Very low density and low density lipoprotein subfractions in type III and type IV hyperlipoproteinemia. Chemical and physical properties.

Subfractions of CLDL (VLDL), Sf 100-400; CLDL2, Sf 60--100; VLDL3, Sf 20--60) and LDL (LDL), Sf 12--20; LDL2, Sf 6--12; LDL3, Sf 3--6) were isolated from the plasma of three normal, three type III and four type IV hyperlipoproteinemic subjects. In the type IV group, all VLDL subspecies were of normal composition but were increased in concentration in the order VLDL1 greater than VLDL2 greater than VLDL3. In the same subjects, although LDL2 was lowered and LDL3 increased, the total plasma LDL concentration was normal. All VLDL subfractions were elevated in the type III group, but in this case VLDL3 predominated. These subfractions were enriched in cholesteryl esters and depleted in triglyceride. In the LDL density range there was a shift of mass towards the least dense fraction, LDL1, which was of normal composition. EPR studies of the VLDL and LDL subfractions in a type IV subject demonstrated a decrease in fluidity with increasing density. The major change occurred between VLDL3 and LDL1 and was attributed to a substantial alteration in the cholesteryl ester : triglyceride ratio in the particle. A similar argument was used to explain thction in normal or type IV subjects. Particle diameters, determined by laser light-scattering spectroscopy were in good agreement with the values obtained by electron microscopy. This study provides a baseline for the examination of the relationship between the physical and metabolic properties of VLDL and LDL subfractions in type III and IV hyperlipoproteinemia.

Apolipoproteins↗
PubMed1979

The effects of cholestyramine on high density lipoprotein metabolism.

This study on 4 type II hyperlipoproteinaemic subjects examines the effects of pharmacologic doses (8 g twice daily) of the bile acid sequestrant cholestyramine on the plasma distribution and chemical composition of the high density lipoprotein subfractions, HDL2 and HDL3, and describes the influence of the drug on the metabolism of the major HDL aporoteins, apolipoprotein A-I and A-II. Cholestyramine lowered plasma low density lipoprotein cholesterol (32%; P less than 0.05) without affecting the level of that lipid in very low density or high density lipoproteins. However, the plasma HDL2/HDL3 ratio and apolipoprotein A-I concentration rose significantly on treatment, while apolipoprotein A-II remained unchanged. The rise in apolipoprotein A-I derived from an increase in its synthetic rate and produced a relative enrichment of the protein with respect to apolipoprotein A-II in both HDL subfractions. These results demonstrate the cholestyramine treatment affects HDL metabolism in a way which, according to current concepts, may prove beneficial to the recipient.

Apolipoproteins↗
PubMed1979

Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism.

This report describes the effects of pharmacologic doses (3 g/d) of nicotinic acid on the plasma distribution and chemical composition of the high density lipoprotein (HDL) subfractions HDL(2) and HDL(3) and examines the influence of the drug on the metabolism of the major HDL apoproteins, apolipoproteins A-I (ApoA-I) and A-II (Apo-II). The drug lowered plasma cholesterol (15%, P < 0.05) and triglyceride (27%, P < 0.01); the former effect a result of a fall in the amount of cholesterol associated with very low density lipoproteins (31%, P < 0.02) and low density lipoproteins (36%, P < 0.02). Conversely, it raised plasma HDL cholesterol (23%, P < 0.05) and increased (by 345%) the plasma HDL(2):HDL(3) ratio. The latter derived from an absolute increment (646%) in circulating HDL(2), coupled with a fall (47%) in HDL(3). This change was not associated with major alterations in the overall cholesterol (free and esterified), triglyceride, phospholipid, or protein content of the subfractions; however, it was accompanied by substantial changes in their protein composition. In particular, the molar ratio of ApoA-I:ApoA-II in HDL(3) declined from 2.7:1 to 2.1:1 during nicotinic acid treatment.Significant perturbations of ApoA-I and ApoA-II metabolism accompanied the drug-induced HDL subfraction redistribution. Specifically, the plasma concentration of ApoA-I rose by 7% (P < 0.05) because of a decrease in its fractional catabolic rate. Moreover, whereas before treatment 6 and 94% of the plasma ApoA-I circulated with HDL(2) and HDL(3), after commencement of nicotinic acid therapy this distribution became 49 and 51% in HDL(2) and HDL(3), respectively. ApoA-II was found mainly in HDL(3), both before and during nicotinic acid treatment. Administration of the drug caused a 14% reduction in its plasma concentration (P < 0.05), which derived principally from a fall (22%, P < 0.01) in its synthetic rate. These data suggest that the effects of nicotinic acid on the HDL subfraction distribution may be mediated via (a) net transfer of ApoA-I from HDL(3) to HDL(2) and (b) a reduction in ApoA-II synthesis. Our present understanding of the association between HDL and atherosclerosis indicates that such changes may have prophylactic value in the prevention of coronary artery disease.

Adult↗
PubMed1979

Receptor-mediated low density lipoprotein catabolism in man.

Binding of human low density lipoproteins (LDL) to their specific receptor on cultured cells can be inhibited by treatment with 1,2-cyclohexanedione which blocks a number of functionally significant arginyl residues on the apolipoprotein. We have used this observation to examine the role of the receptor pathway in LDL catabolism in man. The plasma clearance rates of 125I-LDL and 131I-cyclohexanedione-treated LDL were measured in four normal and four heterozygous familial hypercholesterolemic subjects. Chemical modification of the lipoprotein significantly reduced its fractional clearance rate and permitted calculation of receptor-mediated and receptor independent catabolism in both groups. The normal subjects cleared 11% of their plasma LDL pool (corresponding to 3.0 mg/kg per day) by a receptor-independent path. In tared daily by these pathways, respectively. Because the mean apoLDL pool size in the group was increased 3-fold over normal, this gave absolute clearance rates for the apoprotein of 2.5 mg/kg per day via the receptors and 12.8 mg/kg per day by the nonreceptor pathway. We conclude that the specific LDL receptor mechanism operates in vivo and probably accounts for 33% and 16% of overall LDL catabolism in normal and heterozygous familial hypercholesterolemic subjects, respectively.

Adult↗
PubMed1978

Effects of dietary saturated and polyunsaturated fat on the metabolism of apolipoproteins A-I and B. Study of a patient with type IIb hyperlipoproteinaemia.

The effects of dietary saturated and polyunsaturated fat on the metabolism of apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) were studied in a patient with type IIb hyperlipoproteinaemia. On the saturated fat diet, the rate of synthesis of very low density lipoprotein apoprotein B (VLDL-apoB) was approximately twice normal, accounting for the increased plasma VLDL pool in this subject. However, 54% of the synthesized VLDL-apoB was catabolized by a pathway independent of low density lipoproteins (LDL). The metabolic conversion rate of VLDL-apoB to LDL-apoB was normal in this subject and his expanded plasma LDL-apoB pool resulted, not from increased input of the apoprotein from VLDL, but from a decrease in its fractional clearance rate. On the polyunsaturated diet, there was a significant fall in the plasma cholesterol and triglyceride concentrations and a change in the fatty acid composition of all plasma lipoprotein fractions. These changes were accompanied by a decrease in the plasma concentrations of apoA-I and apoB which resulted from a reduction of apoprotein synthetic rate.

Aged↗
PubMed1978

Metabolism of apolipoproteins A-I and A-II and its influence on the high density lipoprotein subfraction distribution in males and females.

Rate zonal ultracentrifugation of plasma samples from ten healthy age-matched volunteers (five males, five females) indicated that the high density lipoprotein subfraction ratio (HDL2:HDL3) in females was significantly higher than in males. The cause of this phenomenon was investigated by simultaneous examination of the metabolism of the major HDL apoproteins (apoA-I and apoA-II) in both groups. The results show that there is no significant sex-related difference in the plasma pool size, fractional catabolic rate, or synthetic rate of either apoprotein. We conclude that the increased HDL2:HDL3 ratio in femalse versus males does not derive from measurable differences in the metabolic handling of either apoprotein.

Adult↗
PubMed1978

Effects of dietary polyunsaturated and saturated fat on the properties of high density lipoproteins and the metabolism of apolipoprotein A-I.

In this study we have investigated, in four normal males the effects of dietary saturated and polyunsaturated fat on the chemical composition and thermotropic properties of human high density lipoproteins (HDL) and have measured the influence of the diets on the metabolism of that fraction of HDL apolipoprotein A-I (apoA-I) that undergoes exchange in vitro and accounts for approximately two-thirds of the lipoprotein's apoA-I complement. When compared with the saturated fat diet, the polyunsaturated diet reduced plasma cholesterol (24%, P < 0.01) by affecting the cholesterol content in the very low density lipoprotein ( downward arrow25%, P < 0.02), low density lipoprotein ( downward arrow20%, P < 0.01), and high density lipoprotein fractions ( downward arrow33%, P < 0.01). Plasma triglyceride was also lowered (by 13%, P < 0.01). Furthermore, polyunsaturated fat ingestion caused a significant fall in the palmitate and stearate content of HDL triglyceride (41 and 37%, respectively), cholesteryl esters (29 and 35%), and phospholipids (17 and 9%) with a concomitant increase in the linoleate content of these moieties (157, 28, and 29%, respectively). The polyunsaturated diet also produced reciprocal changes in the percentage protein ( downward arrow9%, P < 0.02) and phospholipid ( downward arrow11.5%, P < 0.01) in HDl. These compositional changes were associated with an increase in the microscopic fluidity of the polyunsaturated HDL, although both diets had little effect on the fluidity parameters of HDL at body temperature. Rate zonal ultracentrifugation indicated that the HDL(2)/HDL(3) ratio fell by 28% (P < 0.05) on the polyunsaturated fat diet. In addition to the above, this diet reduced plasma apoA-I by 21% (P < 0.01). No change was seen in the fractional catabolic rate or the distribution of the apoprotein between intravascular and extravascular compartments on the two diets. However, when compared with the saturated diet, the synthetic rate of apoA-I was reduced by 26% during polyunsaturated fat feeding. The results show that polyunsaturated fat alters the chemical composition, thermotropic properties, and subfraction distribution of HDL without changing the fractional rate of catabolism of their major protein, apoA-I.These findings deserve careful consideration in determining the applicability and efficacy of polyunsaturated fat diet therapy in the prevention of atherosclerosis in man.

Adult↗
PubMed1978

Dynamic properties of human high density lipoprotein apoproteins.

This study was designed to identify a method for the measurement of human high density lipoprotein subfraction (HDL2 and HDL3) metabolism. Apolipoproteins A-I, A-II, and C, the major HDL apoproteins, were radioiodinated and incorporated individually into HDL2 and HDL3 in vitro. Using a double label technique, the turnover of apoA-I in HDL2 and HDL3 was measured simultaneously in a normal male. The apoprotein exchanged rapidly between the two subfractions, evidenced by equilibration of their apoA-I specific activity. Radiolabeled apoA-II, incorporated into the subfractions, showed a similar exchange in vitro. Incubation of 131I-labeled very low density lipoproteins (VLDL) with HDL or its subfractions resulted in transfer of C proteins from VLDL to the HDL moiety. The extent of transfer was dependent on the HDL subfraction present; 50% of the VLDL apoC was transferred to HDL3, while the transfer to total HDL and HDL2 was 69% and 78%, respectively. ApoC also exchanged between HDL2 and HDL3, again showing a preference for the former and suggesting a primary metabolic relationship between VLDL and HDL2. Overall, the study indicates that apoA-I, apoA-II, and the C proteins exist in equilibrium between HDL2 and HDL3. This phenomenon precludes their use as probes for HDL subfraction metabolism in humans.

Apolipoproteins↗
PubMed1978

A comparison of two methods to investigate the metabolism of human apolipoproteins A-I and and A-II.

Two methods are compared for measuring the kinetic parameters of apolipoprotein A-I and A-II metabolism in human plasma. In the first, high density lipoprotein apoproteins were radioiodinated in situ in the lipoprotein particle (endogenous apoprotein labeling) while in the second, individually labeled apolipoprotein A-I or A-II was incorporated into the particle by in vitro incubation (exogenous apoprotein labeling). The catabolic clearance rate of exogenously labeled apolipoprotein A-I was consistently faster than that of endogenous apolipoprotein A-I. Conversely, endogenously and exogenously labeled apolipoprotein A-II were catabolized at identical rates. The fractional plasma clearance rates of endogenous apolipoproteins A-I and A-II were the same.

Adult↗
PubMed1977

Electrophoretic mobility in agarose of very low density lipoprotein subfractions in type III hyperlipoproteinaemia.

The electrophoretic mobilities in agarose gel of the very low density lipoprotein (VLDL) subfractions of Sf greater than 100, 60-100 and 20-60 from six subjects with type III hyperlipoproteinaemia (HLP) have been compared with those from eight normal volunteers. In type III HLP beta or near-beta (slower VLDL) electrophoretic mobility was not necessarily confined to the VLDL fraction of Sf 20-60 in which it may normally be detected.

Adult↗
PubMed1976

Low density lipoprotein metabolism in a family of familial hypercholesterolemic patients.

A low-density lipoprotein turnover study was performed on six heteroxygous familial hypercholesterolemic subjects and five control subjects. The diagnosis of the condition was clear-cut on biochemical, clinical, and genetic grounds. Kinetic analysis of the plasma decay curves gave the following mean values: (1) The plasma concentration of low density lipoprotein apoprotein (apoLDL) in the affected subjects was 247 mg/dl, a 2.5-fold increase over control values (98 mg/dl). (2) The calculated fractional catabolic rate of the intravascular apoLDL pool in the dyslipo-proteniemics was reduced with respect to control data (16.4%/day versus 31.2%/day), and the half-life of the apolipoprotein was correspondingly increased (6.07 days versus 3.63 days). (3) The absolute catabolic rate of the apoLDL was 15.6 mg/kg/day in contrast to the lower value of 11.6 mg/kg/day in the control group. (4) A strong negative correlation was observed between the plasma apoLDL concentration and the fractional catabolic rate (r = 0.96). We conclude from our data that increased apoLDL synthesis coupled with a defective or saturated catabolic mechanism is implicated in the pathogenesis of familial hypercholesterolemia.

Adult↗