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L R Miller

Publications and source records attributed to L R Miller.

At least 37 records · Page 2Linked to original sources
PubMed1990

In vivo clearance of low density lipoprotein in pigeons occurs by a receptor-like mechanism that is not down-regulated by cholesterol feeding.

The contribution of receptor-dependent and receptor-independent mechanisms for low density lipoprotein (LDL) clearance in vivo was determined in White Carneau and Show Racer pigeons fed either cholesterol free or cholesterol containing diets. The methylation of pigeon LDL resulted in the inhibition of recognition by the LDL receptor which allowed its use as a tracer of receptor-independent clearance. The fractional catabolic rate (FCR) of radiolabeled LDL in 20 control pigeons (means +/- S.E., 0.277 +/- 0.013 pools/h) was approximately seven times faster than for methylated LDL indicating that 86% of the total LDL clearance occurred by a receptor-mediated process. Total LDL clearance was reduced by 27% (FCR = 0.202 +/- 0.012 pools/h) in 14 cholesterol-fed pigeons, but receptor-mediated mechanisms were still responsible for 80% of the total LDL clearance. LDL uptake by individual tissues was measured using the residualizing label 125I-tyramine cellobiose. The liver was the primary site of LDL clearance in both control and cholesterol-fed birds. LDL receptors were active in every tissue examined and accounted for over 85% of the LDL clearance in the liver and over 90% in the adrenal gland. Consistent with the whole body LDL clearance findings, cholesterol-feeding did not significantly reduce receptor-mediated clearance of 125I-tyramine cellobiose-LDL by the liver or any of the other tissues. Hepatic sterol synthesis, however, was reduced by greater than 90% in cholesterol-fed animals. These data are consistent with the conclusion that LDL clearance in vivo in pigeons is mediated primarily by an LDL receptor-like mechanism that shows little down-regulation with hypercholesterolemia even though cholesterol synthesis is efficiently down-regulated.

Adrenal Glands↗
PubMed1989

Acquired renal cystic disease in end-stage renal disease: an autopsy study of 155 cases.

Autopsy reports on 155 successive end-stage renal disease (ESRD) patients and 147 control patients without ESRD, matched for age, race and gender, were collected. Cystic transformation of the kidneys was noted in 58% of the ESRD patients and 13.6% of the control patients. There were 25 ESRD patients with renal adenoma and 3 with renal cell carcinoma. The single best predictor of cystic transformation or tumorous degeneration was patient's age. A statistically significant association between cystic transformation and gender, as well as the cause of ESRD, was also found. In contrast to previous reports we were unable to document a strong association between the incidence of either cystic transformation or tumorous degeneration with the duration of dialysis, nor did these two parameters correlate with mode of dialysis. We suggest that cystic transformation of the kidneys in ESRD is related to age and renal failure per se, is not strongly associated with duration of dialysis and is independent of mode of dialysis. Concomitant tumorous degeneration was frequent, but this was usually an incidental autopsy finding. Renal malignancy was uncommon and metastases were absent.

Adenoma↗
PubMed1988

Inhibitors of sterol synthesis. Effects of dietary 5 alpha-cholest-8(14)-en-3 beta-ol-15-one on early enzymes in hepatic cholesterol biosynthesis.

The effects of dietary administration (0.1% in diet for 8 days) of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one on the levels of activity of cytosolic acetoacetyl coenzyme A thiolase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, and microsomal HMG-CoA reductase in liver have been studied in male Sprague-Dawley rats. Significant increases in the levels of activity of acetoacetyl-CoA thiolase and of HMG-CoA synthase were observed. The levels of microsomal HMG-CoA reductase activity were increased, relative to pair-fed control animals, in three experiments and increased, relative to ad libitum control animals, in one of three experiments. When compared with other agents for which the primary mode of action is an inhibition of the intestinal absorption of cholesterol, the magnitude of the increases in the levels of hepatic microsomal HMG-CoA reductase activity in the 15-ketosterol-fed rats was considerably smaller. In view of the previously described marked activity of the 15-ketosterol in the inhibition of the intestinal absorption of cholesterol, as well as its known effects in lowering HMG-CoA reductase activity in mammalian cells in culture, it is proposed that the 15-ketosterol may suppress the elevated levels of hepatic microsomal HMG-CoA reductase activity induced by the reduced delivery of cholesterol to liver as a consequence of the inhibition of the intestinal absorption of cholesterol.

Acetyl-CoA C-Acetyltransferase↗
PubMed1988

Inhibitors of sterol synthesis. Studies of the metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one in Chinese hamster ovary cells and its effects on activities of early enzymes in cholesterol biosynthesis.

The metabolism of [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one (I) has been studied in Chinese hamster ovary (CHO-K1) cells which were maintained in a lipid-deficient medium. The incorporation of I into the cells was linear with respect to sterol concentration in the medium over the ranges of concentrations studied and was more than 3.5 times that of the uptake of cholesterol. The results of detailed chromatographic analyses of the lipids recovered from the cells after 6 h of incubation with [2,4-3H]I (0.5 microM or 6.0 microM) indicated that most of the 3H was associated with free I. Considerably lesser amounts of the 3H was associated with esters of I. No formation of [3H]cholesterol or [3H]cholesteryl esters (or other C27 monohydroxysterols) from labeled I was observed. The labeled material with the chromatographic behavior of the esters of I gave, after mild alkaline hydrolysis, the free 15-ketosterol which was characterized by the results of chromatographic and cocrystallization studies. Upon transfer of the CHO-K1 cells from a culture medium containing 8% newborn calf serum to the same medium containing 8% lipid-deficient newborn calf serum, increases in the levels of activity of cytosolic acetoacetyl-CoA thiolase and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and of HMG-CoA reductase were observed. These increases were blocked by the addition of I at a concentration of 1.0 microM. I (1.0 microM) also caused a decrease in the levels of activity of the three enzymes in cells previously grown in medium containing lipid-deficient serum. These results demonstrate that I not only affects the enzymatic reduction of HMG-CoA but also the enzymatic formation of this key intermediate in cholesterol biosynthesis.

Acetyl-CoA C-Acetyltransferase↗
PubMed1987

5 alpha-cholest-8(14)-en-3 beta-ol-15-one. A competitive substrate for acyl coenzyme A:cholesterol acyl transferase.

5 alpha-Cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of cholesterol biosynthesis with hypocholesterolemic activity, has been found to serve as an efficient substrate for acyl CoA:cholesterol acyl transferase of rat hepatic and jejunal microsomes and to inhibit the esterification of cholesterol. Concentrations required to give 50% inhibition of cholesterol ester formation in liver and jejunal microsomes were approximately 10 microM and approximately 3 microM, respectively.

Animals↗
PubMed1987

Evidence for the existence of a lateral cervical nucleus in mice, guinea pigs, and rabbits.

The lateral cervical nucleus of carnivores is large and is thought to play a prominent role in somatosensory processing. In contrast, early studies indicated that rats, mice, guinea pigs, and rabbits did not have a lateral cervical nucleus. However, we reported the existence of a lateral cervical nucleus in rats as a result of studies using retrograde transport techniques. In the present study, similar techniques were used to examine the possibility that early studies also overlooked the lateral cervical nucleus in mice, guinea pigs, and rabbits. In each of these species, a retrograde tracer was injected into the thalamus. These injections labeled a small number of neurons contralaterally in the dorsal part of the lateral funiculi of rostral cervical segments. Mice had the greatest number of neurons projecting from the lateral cervical nucleus to the thalamus, and rabbits had the fewest.

Animals↗
PubMed1985

Lupus lung.

The morphologic findings from 18 autopsy lungs of systemic lupus erythematosus were studied. Each case revealed varying degrees of pleuropulmonary disease. A universal feature was visceral pleural thickening, while findings present in more than one half of the cases included pulmonary congestion (17/18) and edema (15/18), pleural adhesions (11/18) and pleural effusions (10/18) and intraalveolar hemorrhage (10/18). Also seen were bronchopneumonia (9/18), interstitial fibrosis (6/18), cytomegalovirus infection (3/18), interstitial pneumonitis (2/18), hyaline membranes (2/18), and acute vasculitis (1/18) and pleuritis (1/18). These results, together with those of previously reported studies of lupus lung, establish that although certain characteristic pleuropulmonary disease processes are frequently found at autopsy, none is a highly specific marker for the disease.

Adolescent↗
PubMed1983

Purification and crystallization of mammalian lens gamma-crystallins.

Monomeric crystallins, beta s and several members of the gamma-crystallin family, occur in different relative proportions in a way which is related to the age of the lens cells. Methods of purification of large amounts of these different low molecular weight protein components from young and old bovine lenses are described along with details of crystallization of several gamma-fractions. Purification procedures have been developed for rabbit gamma-crystallins. The chromatographic methods achieve separation of several bovine and rabbit gamma-crystallins which have very similar electrophoretic mobilities. However, on storage, many electrophoretic variants are generated from some of these fractions.

Aging↗
PubMed1983

Fetal iron balance in the rat.

Maternal and fetal iron balance through pregnancy was examined in the rat. The 20th day was selected for detailed study because of the peak iron requirements at that time. The standard diet provided a borderline iron supply to the fetus due to the limited availability of its iron for absorption. When a more available form of iron was used, normal fetal development occurred over a range of dietary iron content from 16 to 2500 mg/kg. At a level of 5 to 8 mg/kg, there was attrition of placental tissues with frequent fetal death and resorption. When the iron-deficient pregnancy was sustained, both maternal and fetal iron deficiency were present. At progressively higher levels of dietary iron, feto-placental iron content was constant despite a progressive increase in maternal iron stores. Fetal iron supply appeared to be determined primarily by plasma iron concentration, and, at normal levels, about 25% of transferrin iron passing through the uterine vasculature, was removed by the intact placentas. Low levels of plasma iron resulted in damage to fetal tissues and reduced the capacity of placental tissues to take up iron. At high levels of plasma iron, plasma iron turnover initially increased 5-fold over basal levels in nonpregnant animals due to increased placental uptake. However, with continued hyperferremia, uptake was regulated so as to maintain fetal iron at a normal level. A comparison of these data with human iron requirements explained the occurrence of both maternal and fetal iron deficiency in the rat, but only maternal iron deficiency in the human.

Animals↗
PubMed1981

Inhibitors of sterol synthesis. Differential effects of 14 alpha-hydroxymethyl-5 alpha-cholest-7-ene-3 beta, 15 alpha-diol and 14 alpha-hydroxymethyl-5 alpha-cholest-6-ene-3 beta, 15 alpha-diol on sterol synthesis in cell-free homogenates of rat liver.

14 alpha-Hydroxymethyl-5 alpha-cholest-7-ene-3 beta, 15 alpha-diol and 14 alpha-hydroxymethyl-5 alpha-cholest-6-ene-3 beta, 15 alpha-diol have been shown to be potent inhibitors of the synthesis of digitonin-precipitable sterols in mouse L-cells and in primary cultures of fetal mouse liver cells and to cause a reduction in the levels of activity of 3-hydroxy-3-methylglutaryl-CoA reductase in the same cells (Schroepfer, G. J., Jr., Parish, E. J., Pascal, R. A., Jr., and Kandutsch, A. A. (1980) J. Lipid Res. 21, 571-584). In the present study, we have found that both sterols have a second, but distinct, site of action, distal to the formation of mevalonic acid. 14 alpha-Hydroxymethyl-5 alpha-cholest-7-ene-3 beta, 15 alpha-diol has been found to be a potent inhibitor of the synthesis of digitonin-precipitable sterols from labeled mevalonate in cell-free preparations of rat liver. This inhibition was accompanied by a striking accumulation of labeled lanosterol and 24,25-dihydrolanosterol. The latter sterols were fully characterized by the results of chromatographic and co-crystallization experiments. In contrast, 14 alpha-hydroxymethyl-5 alpha-cholest-6-ene-3 beta, 15 alpha-diol had only a slight effect on the synthesis of digitonin-precipitable sterols from labeled mevalonate in cell-free rat liver preparations. The delta 6-3 beta, 15 alpha, 32-triol had no apparent effect on the metabolism of lanosterol and 24,25-dihydrolanosterol but caused a substantial accumulation of labeled 5 alpha-cholest-8-en-3 beta-ol which was fully characterized by the results of chromatographic and co-crystallization experiments. These findings are compatible with a specific inhibition of the metabolism of lanosterol and 24,25-dihydrolanosterol by the delta 7-3 beta, 15 alpha, 32-triol and a specific inhibition of the delta 8 leads to delta 7 isomerase by the delta 6-3 beta, 15 alpha, 32-triol. [2,4]3H]14 alpha-Hydroxymethyl-5 alpha-cholest-7-ene-3 beta, 15 alpha-diol, prepared by chemical synthesis, was not convertible to cholesterol upon incubation, under aerobic conditions, with a cell-free homogenate preparation of rat liver. The labeled delta 7-3 beta, 15 alpha, 32-triol was, however, metabolized to several polar compounds.

Animals↗
PubMed1980

Cycloheximide inhibits sterol biosynthesis in cell-free preparations of rat liver.

Cycloheximide, frequently used as an inhibitor of protein synthesis in vivo and in vitro, has been found to cause a significant reduction of the synthesis of digitonin-precipitable sterols from acetate, but not from mevalonate, at a concentration of 1 mM in the 10,000 x g supernatant fraction of rat liver homogenate preparations. The results of studies of the metabolism of labeled leucine under the same conditions indicated that the effect of cycloheximide on sterol synthesis from acetate was not related to an effect of cycloheximide on protein synthesis. Preincubation of the 10,000 x g supernatant fraction of rat liver homogenates with cycloheximide (1 mM) caused a significant reduction in the levels of acetate thiokinase and hydroxymethylglutaryl-CoA synthase activities but not of acetoacetyl-CoA thiolase activity. Preincubation of the 100,000 x g supernatant fraction of rat liver homogenates with cycloheximide (1 mM or 0.3 mM) also caused a significant reduction of the levels of hydroxymethylglutaryl-CoA synthase activity. When cycloheximide (1 mM) was preincubated with the 100,000 x g supernatant fraction, a reduction in the level of acetate thiokinase activity was observed. Preincubation of rat liver microsomes with cycloheximide (1 mM and 3 mM) had no effect on the level of hydroxymethylglutaryl-CoA reductase activity. These results suggest that biological effects observed upon exposure of cells or tissues to high concentrations of cycloheximide may not be exclusively due to effects of the cycloheximide on the synthesis of protein.

Acetates↗
PubMed1979

Lactic acidosis as a result of iron deficiency.

Iron-deficient rats have an impaired work performance, even when their anemia is corrected by exchange transfusion. Muscle activity is associated with a higher blood lactate concentration than is observed in iron-replete animals. The accumulation of lactate is a result of excessive production as lactate clearance from the blood was shown to be unaffected. By adjusting the work load to a lower level, it was possible to divide iron-deficient animals into two groups, one capable of continued treadmill running and another in which animals stopped before 20 min. In the former, blood lactate concentration reached a plateau at moderate levels, whereas it continued to increase in the latter until the animal stopped running. Levels of alpha-glycerophosphate oxidase in skeletal muscle mitochondria were found to be much lower in the second group (P < 0.001). Lactate infusion into normal animals was shown to interfere with work performance, and maintenance of a normal pH in iron-deficient and iron-replete animals did not prevent the impairment in work associated with high blood lactate concentrations. Additional evidence was obtained that energy substrate (blood glucose and free fatty acids, muscle glycogen) was adequate in irondeficient animals. Oxygen tension in their vena caval blood was higher than in controls. Furthermore, the in situ behavior of electrically stimulated gastroenemius and soleus muscles appeared similar to that of control animals. Because the stimulation of the single muscle in the iron-deficient animal did not result in appreciable elevation of blood lactate and did not show impaired contractility further supported the hypothesis that the elevation of blood lactate caused the decreased work performance. It is concluded that iron deficiency by a depletion in the iron-containing mitochondrial enzyme, alpha-glycerophosphate oxidase, impairs glycolysis, resulting in excess lactate formation, which at high levels leads to cessation of physical activity.

Acidosis↗
PubMed1979

Iron deficiency in the rat: effects on phenylalanine metabolism.

Concentrations of phenylalanine in the plasma were markedly elevated in iron-deficient rats and appeared to vary directly with the degree of iron deficiency. Plasma concentrations of phenylalanine returned to control levels within one week after treatment of the iron-deficient rats with iron dextran. The elevated levels of plasma phenylalanine were probably not produced by a deficiency in liver phenylalanine hydroxylase because levels of activity of the enzyme were found to be normal in the livers of the iron-deficient animals.

Animals↗