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Biomedical subjects

R J Havel

Publications and source records attributed to R J Havel.

At least 127 records · Page 7Linked to original sources
PubMed1982

Serum apolipoprotein A-I levels: relationship to lipoprotein lipid levels and selected demographic variables.

Serum apolipoprotein A-I (apo A-I) and lipoprotein cholesterol and triglycerides were measured in 289 persons randomly selected from a Northern California industrial population in 1974-1976. Apo A-I and high density lipoprotein (HDL) cholesterol were strongly correlates with one another and both were inversely correlated with very low density lipoprotein (VLDL) triglycerides. The decrease in HDL-cholesterol with increasing VLDL-triglycerides was relatively much larger than the concomitant decrease in apo A-I. The relative decrease in the sum of cholesterol and triglycerides in the HDL fraction was similar to that for apo A-I, suggesting that the decreasing HDL-cholesterol:apo A-I ratio with increasing VLDL-triglycerides is due in large part to reciprocal transfer of cholesteryl esters for triglycerides between HDL and VLDL. Mean apo A-I level was 16 mg/dl higher in women not taking exogenous sex steroids than in men, 31 mg/dl higher in women taking estrogens without progestins and 10 mg/dl higher in contraceptive drug users than in other women, and 8 mg/dl higher in black than in white men. The first two of these differences were statistically significant. Apo A-I level was unrelated to age, but increased with ethanol consumption and decreased with adiposity. An inverse relationship between Apo A-I and cigarette smoking was found among women.

Adult↗
PubMed1982

Secretion of nascent lipoproteins and apolipoproteins by perfused livers of normal and cholesterol-fed guinea pigs.

Triglyceride-rich very low density lipoproteins (VLDL) are the major lipoprotein in perfusates of normal guinea pig livers. Their component apoprotein B is mainly B-100 together with some B-95. This apoprotein is actively synthesized, as are C apoproteins and small amounts of apoprotein E. Only trace amounts of intermediate density lipoproteins (IDL, 1.015 < d < 1.05 g/ml) are found in perfusates, but appreciable amounts of low density lipoproteins (LDL, 1.05 < d < 1.10 g/ml) accumulate. These LDL are not newly synthesized, but rather appear to be gradually washed out of the liver. High density lipoproteins (HDL, 1.10 < d < 1.21 g/ml) both discoidal and spheroidal, also accumulate, which contain newly synthesized apoproteins A-I, E and C. Fatty livers of guinea pigs fed cholesterol secrete less VLDL and more IDL than normals, but the combined amount of protein is unchanged. These lipoproteins contain newly synthesized apoprotein B, are enriched in cholesteryl esters and newly synthesized apoprotein E, and have reduced electrophoretic mobilities, making them resemble remnants. Large amounts of LDL also accumulate in perfusates of livers from cholesterol-fed animals, much of which does not appear to be newly synthesized, as judged from single pass perfusions. However, the LDL fraction is complex and includes particles that contain newly synthesized apoprotein B. Thus, these livers appear to secrete a spectrum of cholesteryl ester-rich particles, containing newly synthesized apoproteins B and E that span the density range of VLDL, IDL, and LDL. Livers of cholesterol-fed guinea pigs secrete large amounts of discoidal HDL with a free cholesterol-phospholipid molar ratio of 2:1. Accumulation of protein (almost entirely newly synthesized apoprotein E) in HDL is increased 25-fold over that in perfusates from normal guinea pig livers.-Guo, L.S.S., R.L. Hamilton, R. Ostwald, and R. J. Havel. Secretion of nascent lipoproteins and apolipoproteins by perfused livers of normal and cholesterol-fed guinea pigs.

Animals↗
PubMed1981

Metabolism of chromatographically separated rat serum lipoproteins specifically labeled with 125I-apolipoprotein E.

Radioiodinated apolipoprotein E, added in small amounts to rat serum, rapidly associates with the serum very low density lipoproteins and high density lipoproteins in proportion to their content of endogenous and apolipoprotein E. The labeled lipoproteins can be separated, without ultracentrifugation, by molecular sieve chromatography. When these labeled lipoproteins are injected intravenously into intact rats, the labeled apolipoprotein E rapidly exchanges with apolipoprotein E in the alternate lipoprotein fraction and is removed from the blood at a slow rate, comparable to that observed for apolipoprotein A-I in similarly labeled high density lipoproteins. No evidence was found for a rapidly turning over component of high density lipoproteins containing apolipoprotein E. When very low density lipoproteins, labeled endogenously with [3H]cholesterol and with radioiodinated apolipoprotein E, are added to perfusates of isolated rat livers, the labeled cholesteryl esters and apolipoprotein E are removed from the perfusate rapidly and at the same rate. Therefore, the slow removal of labeled apolipoprotein E in very low density lipoproteins in vivo is the result of rapid exchange with apolipoprotein E in high density lipoproteins.

Animals↗
PubMed1981

Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen.

We studied the effect of th bite acid sequestrant colestipol, alone and in combination with clofibrate or niacin, in patients with heterozygous familial hypercholesterolemia who were given a diet low in cholesterol and saturated fat. With colestipol alone, mean cholesterol levels in serum decreased 16 to 25 per cent. The addition of clofibrate produced a total mean decrement of only 28 per cent. In contrast, serum cholesterol levels fell 45 per cent when colestipol as combined with niacin. Low-density-lipoprotein (LDL) cholesterol decreased 55 per cent with colestipol and niacin, whereas high-density-lipoprotein (HDL) cholesterol increased. Mean LDL cholesterol was lower in patients given this regimen than in matched normal controls eating an unrestricted diet. Tendinous xanthomas, measured by quantitative xeroradiography, were significantly reduced (P < 0.01), indicating that this regimen mobilized cholesterol from tissue pools with slow turnover. Colestipol plus niacin promises to be useful in the treatment of patients at high risk from elevated levels of LDL.

Adult↗
PubMed1981

On the extravascular pool of low-density lipoprotein in rat liver.

1. The mass of the extravascular pool of low-density lipoprotein (LDL) in liver was measured in rats injected intravenously with radioiodinated LDL by determining the radioactive iodine remaining in the extravascular tissues of liver and in plasma when the hepatic intravascular and extravascular radioactive iodine had equilibrated (equilibrium-time method). 2. The mass of the extravascular pool of LDL in the liver was about 6% of the total intravascular pool. Total extravascular pool of LDL in eight rats, obtained by multicompartmental analysis of the time-curve of disappearance of radioiodinated LDL from blood plasma, was 43 +/- 15% (mean +/- SD) of the intravascular pool. 3. Hence the hepatic extravascular pool comprises only about 14% of the total extravascular pool of LDL in the rat.

Animals↗
PubMed1981

Autoradiographic localization of the sites of uptake, cellular transport, and catabolism of low density lipoproteins in the liver of normal and estrogen-treated rats.

The hepatic uptake and catabolism of low density lipoproteins are stimulated severalfold in rats treated with large amounts of 17alpha-ethinylestradiol. To determine the sites within the liver at which these processes occur, (125)I-labeled human low density lipoproteins were injected intravenously into intact control and estradiol-treated rats or added to perfusates of their isolated livers. The livers were fixed by perfusion and processed for light and electron microscopic autoradiography. Distribution of autoradiographic silver grains was estimated qualitatively in light micrographs and quantitatively in electron micrographs. Many more silver grains were seen in livers from estradiol-treated than from control rats, but the processing of labeled low density lipoprotein was indistinguishable. Three minutes after intravenous injection or perfusion of livers, the grains were concentrated over the microvillous surface of parenchymal cells bordering the space of Disse. Many of these grains were within two half-distances from endocytic pits. Only 5-15% of the grains were seen over endothelial and Kupffer cells. Silver grains were also observed over vesicles beneath the plasma membrane whose size and shape suggested that they were derived from fusion of endocytic vesicles. By 15 min, grains were predominantly located in structures like multivesicular bodies in the region of the GERL (Golgi complex-endoplasmic reticulum-lysosomes) near the bile canaliculi. These bodies were packed with small vesicle-like structures and a few larger vesicles, the latter possessing a unit membrane. Between 15 and 30 min, when proteolysis of low density lipoproteins is known to begin, the initially clear matrix of the multivesicular body-like structures became dark and the structures frequently had a dense tail-like appendage. At the same time, silver grains began to appear over secondary lysosomes. These and other results indicate that the hepatic uptake of low density lipoproteins that is stimulated in rats given large amounts of estradiol follows a pathway that closely resembles that of the well-defined "LDL receptor" in cultured cells. In the liver these lipoproteins appear to be transported in endocytic vesicles; the vesicles fuse to form multivesicular body-like structures that acquire lysosomal enzymes and are converted to secondary lysosomes as the lipoproteins are degraded.

Animals↗
PubMed1981

Mouse macrophages synthesize and secrete a protein resembling apolipoprotein E.

Monolayers of mouse peritoneal macrophages were shown to synthesize and secrete a protein that resembles apoprotein E (apoE), a normal constituent of plasma lipoproteins. Synthesis and secretion were studied by incubation of macrophages with L-[35S]methionine and analysis of the 35S-labeled proteins secreted into the culture medium. The 35S-labeled protein resembling apoE showed the following properties: (i) it floated in the ultracentrifuge at a density less than 1.215 g/ml, indicating that it was associated with lipid; (ii) by NaDodSO4/polyacrylamide gel electrophoresis, its Mr of 35,000 was identical to that of authentic apoE obtained from mouse plasma very low density lipoprotein; (iii) its isoelectric point of 5.4 was the same as that of authentic mouse apoE; (iv) it comigrated with authentic mouse apoE after two-dimensional isoelectric focusing/NaDodSO4/polyacrylamide gel electrophoresis; and (v) it was quantitatively precipitated by a monospecific antibody directed against rat apoE. Synthesis and secretion of the apoE-like protein was stimulated 3- to 8-fold when the macrophages were loaded with cholesterol by incubation with either acetylated low density lipoprotein (acetyl-LDL) or beta-migrating very low density lipoprotein from cholesterol-fed rabbits. When the cells were incubated with acetyl-LDL, the apoE-like protein composed approximately 2% of the total 35S-labeled protein synthesized by the cells and approximately 10% of the total 35S-labeled protein secreted into the medium. The current findings suggest a role for apoE in the plasma transport of cholesterol excreted from cholesterol-loaded macrophages.

Animals↗
PubMed1981

Metabolism of apolipoprotein A-I of chylomicrons in rats and humans.

After intravenous injection of a large amount of small chylomicrons into intact rats, the concentration of apolipoprotein (apo) A-I was increased by about 40% and remained at this elevated level as most of the chylomicron triglycerides were removed from plasma during the ensuing hour. This apo A-I rapidly left the chylomicrons and was transferred to lipoproteins of higher density. Such transfer of apo A-I did not occur when chylomicrons were incubated at comparably high concentrations with rat serum. In normolipidemic humans, the concentration of apo A-I and apo A-II, as well as phospholipids, increased in the light subfraction of high density lipoproteins (HDL2) 4 to 7 h after ingestion of a meal containing 1.5 g cream fat per kilogram body weight. The concentration of these components increased in the heavy subfraction of high density lipoproteins (HDL3) after 12 to 24 h. The concentration of apo E in plasma was unaffected by fat ingestion, but the concentration of this protein increased in lipoproteins of density less than 1.006 g . mL-1 and fell in lipoproteins of higher density. It is concluded that apo A-I in rat chylomicrons is transferred quantitatively to HDL as chylomicron remnants are formed. Chylomicron apo A-I and apo A-II appear to be transferred similarly to HDL in humans, whereas apo E is transferred from HDL to chylomicrons after chylomicrons enter the blood.

Adult↗
PubMed1981

Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows.

Patients with familial dysbetalipoproteinemia (F. Dys.), also called familial type 3 hyperlipoproteinemia, are homozygous for a mutant allele, Ed, that specifies an abnormal form of apoprotein (apo) E, a prominent constituent of remnant lipoproteins derived from very low density lipoproteins (VLDL) and chylomicrons. Apo E is thought to mediate the removal of remnant lipoproteins from the plasma by virtue of its ability to bind to hepatic lipoprotein receptors. In F. Dys. patients, remnant-like lipoproteins accumulate, apparently because of delayed clearance by the liver. In the current studies, we show that the abnormal protein specified by the Ed allele (apo E-D) from some, but not all, patients with F. Dys. has a markedly deficient ability to bind to low density lipoprotein (LDL) receptors. Apo E was isolated from eight control subjects and nine patients with F. Dys. and incorporated into phospholipid complexes. The complexes were tested for their ability to compete with human 125I-LDL or rabbit 125I-beta-VLDL fo binding to LDL receptors in four assay systems: cultured human fibroblasts, solubilized receptors from bovine adrenal cortex, liver membranes from rats treated with 17 alpha-ethinyl estradiol, and liver membranes from normal rabbits. The apo E-D from six of the nine patients with F. Dys. showed binding affinities for LDL receptors that were reduced by greater than 98% in all receptor assays (group 1 patients). All of these group 1 patients were unequivocally of phenotype apo E-D/D by the criterion of isoelectric focussing. The apo E from the three other F. Dys. patients showed a near normal binding ability in all four of the receptor assays (group 2 patients). One of these group 2 patients appeared to have the apo E-D/D phenotype by isoelectric focussing. In the other two patients in group 2, apo E-D was the predominant protein (phenotype, apo E-D/D), but traces of protein in the region corresponding to normal apo E (apo E-N) were also present. The difference between group 1 and group 2 patients was also apparent when the apo E was iodinated and tested directly for binding to liver membranes from rats treated with 17 alpha-ethinyl estradiol. The 125I-labeled apo E from a group 2 patient, but not a group 1 patient, showed enhanced uptake when perfused through the liver of an estradiol-treated rate, indicating that the receptor binding ability of apo E correlated with uptake in the intact liver. The current studies allow the subdivision of patients with F. Dys. into two groups. In group 1, the elevated plasma level of remnants appears to be due to a diminished receptor binding activity of the abnormal protein specified by the Ed allele; in group 2 patients, the cause of the elevated plasma level of remnants remains to be explained.

Adrenal Glands↗
PubMed1980

The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E.

Hepatic catabolism of lipoproteins containing apolipoproteins B or E is enhanced in rats treated with pharmacologic doses of 17 alpha-ethinyl estradiol. Liver membranes prepared from these rats exhibit an increased number of receptor sites that bind 125I-labeled human low density lipoproteins (LDL) in vitro. In the present studies, this estradiol-stimulated hepatic receptor was shown to recognize the following rat lipoproteins: LDL, very low density lipoproteins obtained from liver perfusates (hepatic VLDL), and VLDL-remnants prepared by intravenous injection of hepatic VLDL into functionally eviscerated rats. The receptor also recognized synthetic lamellar complexes of lecithin and rat apoprotein E as well as canine high density lipoproteins containing apoprotein E (apo E-HDLc). It did not recognize human HDL or rat HDL deficient in apoprotein E. Much smaller amounts of this high affinity binding site were also found on liver membranes from untreated rats, the number of such sites increasing more than 10-fold after the animals were treated with estradiol. Each of the rat lipoproteins recognized by this receptor was taken up more rapidly by perfused livers from estrogen-treated rats. In addition, enrichment of hepatic VLDL with C-apoproteins lowered the ability of these lipoproteins to bind to the estradiol-stimulated receptor and diminished their rate of uptake by the perfused liver of estrogen-treated rats, just as it did in normal rats. The current data indicate that under the influence of pharmacologic doses of estradiol the liver of the rat contains increased amounts of a functional lipoprotein receptor that binds lipoproteins containing apoproteins B and E. This hepatic lipoprotein receptor appears to mediate the uptake and degradation of lipoproteins by the normal liver as well as the liver of estradiol-treated rats. The hepatic receptor bears a close functional resemblance to the LDL receptor previously characterized on extrahepatic cells.

Animals↗
PubMed1980

Determinants of hepatic uptake of triglyceride-rich lipoproteins and their remnants in the rat.

The uptake and metabolism of lymphatic large chylomicrons from fat-fed rats, lymphatic small chylomicrons from glucose-fed rats, and hepatic very low density lipoproteins from perfusates of isolated livers, and of remnants produced from these lipoproteins in functionally eviscerated rats were studied in the isolated perfused rat liver. All lipoproteins were labeled isotopically in their cholesteryl ester and triglyceride moieties. Uptake of the labeled lipids or large chylomicrons was slow and limited, but these lipids in small chylomicrons and hepatic very low density lipoproteins were taken up and metabolized progressively and at equal rates. Incubation with very low density lipoprotein-free plasma increased the content of C apolipoproteins in small chylomicrons and hepatic very low density lipoproteins and greatly retarded the hepatic uptake of their labeled lipids. In remnants from all sources, which are depleted of C apolipoproteins but not of apolipoprotein E, the labeled lipids were rapidly taken up and metabolized. Neither extensive hydrolysis of core triglycerides nor the production of monoglycerides was required for this rapid hepatic uptake. These results are consistent with the hypothesis that one or more of the C apolipoproteins opposes and apolipoprotein E promotes recognition of triglyceride-rich lipoproteins by a hepatic receptor.

Animals↗
PubMed1980

Pancreatic alpha and beta cell function in familial dysbetalipoproteinemia.

Resistance to both insulin and glucagon have been considered as possible causes of primary hypertriglyceridemia. In the present research, we have compared insulin and glucagon secretion in five hyperlipidemic patients with familial dysbetalipoproteinemia with five normolipidemic control subjects matched for age, sex and adiposioty. Plasma insulin and glucagon concentrations mesaured during standard oral glucose tolerance and arginine infusion tests were similar in the two groups. Blood glucose fell transiently in the controls, but not in the patients, during the Himsworth test (100 g glucose orally plus 0.05 U insulin per kg body weight intravenously). There were no significant differences in plasma FFA concentrations and responses during all tests between the groups. The percentage reduction in plasma triglyceride concentration during infusion of arginine was similar in the two groups. These results suggest that the patients with familial dysbetalipoproteinemia were slightly less insulin sensitive than the controls. However, primary insensitivity to glucagon or insulin does not appear to be fundamental to the pathogenesis of hyperlipidemia in familial dysbetalipoproteinemia.

Adult↗