[Treatment of hypercholesterolemia in adults. An action plan].
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Adult↗
Biomedical subjects
K R Norum
Publications and source records attributed to K R Norum.
Uptake of LDL in parenchymal and non-parenchymal rabbit liver cells in vivo. LDL uptake is increased in endothelial cells in cholesterol-fed rabbits.
1. Hepatic uptake of low-density lipoprotein (LDL) in parenchymal cells and non-parenchymal cells was studied in control-fed and cholesterol-fed rabbits after intravenous injection of radioiodinated native LDL (125I-TC-LDL) and methylated LDL (131I-TC-MetLDL). 2. LDL was taken up by rabbit liver parenchymal cells, as well as by endothelial and Kupffer cells. Parenchymal cells, however, were responsible for 92% of the hepatic LDL uptake. 3. Of LDL in the hepatocytes, 89% was taken up via the B,E receptor, whereas 16% and 32% of the uptake of LDL in liver endothelial cells and Kupffer cells, respectively, was B,E receptor-dependent. 4. Cholesterol feeding markedly reduced B,E receptor-mediated uptake of LDL in parenchymal liver cells and in Kupffer cells, to 19% and 29% of controls, respectively. Total uptake of LDL in liver endothelial cells was increased about 2-fold. This increased uptake is probably mediated via the scavenger receptor. The B,E receptor-independent association of LDL with parenchymal cells was not affected by the cholesterol feeding. 5. It is concluded that the B,E receptor is located in parenchymal as well as in the non-parenchymal rabbit liver cells, and that this receptor is down-regulated by cholesterol feeding. Parenchymal cells are the main site of hepatic uptake of LDL, both under normal conditions and when the number of B,E receptors is down-regulated by cholesterol feeding. In addition, LDL is taken up by B,E receptor-independent mechanism(s) in rabbit liver parenchymal, endothelial and Kupffer cells. The non-parenchymal liver cells may play a quantitatively important role when the concentration of circulating LDL is maintained at a high level in plasma, being responsible for 26% of hepatic uptake of LDL in cholesterol-fed rabbits as compared with 8% in control-fed rabbits. The proportion of hepatic LDL uptake in endothelial cells was greater than 5-fold higher in the diet-induced hypercholesterolaemic rabbits than in controls.
Animals↗
[Non-pharmacological treatment of mild to moderate hypertension. A randomized, controlled study--results 1 1/2 years later].
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Adult↗
Retinol bound to physiological carrier molecules regulates growth and differentiation of myeloid leukemic cells.
We have tested effects of retinol bound to its physiological carrier molecules, i.e. low density lipoprotein chylomicron remnants, and retinol binding protein (RBP) on differentiation and proliferation of myeloid leukemic cells in concentrations that can be obtained in vivo. Data presented in this study show that physiological concentrations of retinyl ester in chylomicron remnants induce differentiation and inhibit proliferation of the cell line HL-60 and promyelocytic leukemic cells in primary culture. Retinyl ester in low density lipoprotein showed no effect either on cell differentiation or proliferation of any of the myeloid cells tested. Retinol bound to RBP induced differentiation of HL-60 cells only in concentrations above those that can be found in vivo. However, cell proliferation was reduced both in HL-60 cells and in primary culture of leukemic cells using physiological concentrations of holo-RBP. These results suggest that retinyl ester in chylomicron remnants is the most effective vehicle for transport of retinol into leukemic cells in vivo.
Adult↗
Effect of cytostatics on liver retinol store in rat.
The effect of the cytostatics doxorubicin, 6-thioguanine and cytarabine on retinol store in rat liver was examined. When rats were treated with pharmacological doses of the combination of doxorubicin and 6-thioguanine for 10 days, the content of retinol in the liver was reduced by about 33%. In a longer term experiment, doxorubicin and cytarabine given separately reduced the retinol store by 33% and 11%, respectively, while doxorubicin and 6-thioguanine given in combination reduced retinol in liver by 31%. For one of the cytostatics (doxorubicin) the effects on plasma retinol and on acyl CoA:retinol acyltransferase (ARAT) activity in small intestine were also examined. Both were transiently reduced during the experiment.
Acyltransferases↗
Transfer of retinol from parenchymal to stellate cells in liver is mediated by retinol-binding protein.
Newly absorbed chylomicron remnant retinyl ester is endocytosed by parenchymal liver cells, and retinol is subsequently transferred to perisinusoidal stellate cells in liver. In the present study we have used several approaches to elucidate the mechanism for the paracrine transfer of retinol between liver parenchymal and stellate cells. In one series of experiments, chylomicrons labeled with [3H]retinyl palmitate or with retinyl [3H]palmitate were injected intravenously into rats. It was shown that the retinol as well as the palmitate moiety were initially taken up in parenchymal liver cells. However, only the retinol moiety was detected in stellate cells, indicating that the retinyl ester is hydrolyzed before retinol is transferred to stellate cells. It is well known that parenchymal liver cells secrete retinol bound to retinol-binding protein (RBP), and we have recently found that stellate cells do have RBP receptors. Here we report that antibodies against RBP completely block the transfer of retinol from parenchymal to stellate cells. These findings indicate that following uptake of chylomicron remnant retinyl ester in parenchymal cells, the retinyl ester is hydrolyzed, and retinol secreted from parenchymal cells on RBP is taken up by stellate cells by means of RBP receptors.
Animals↗
Distribution of retinol in rat liver cells: effect of age, sex and nutritional status.
1. We have recently shown that the stellate cells, under normal conditions, contain a majority (more than 80%) of the total store of retinol in liver (Blomhoff et al. 1985). 2. In the present work we have studied the role of the various liver cells in rats of different ages, sex and vitamin A status. 3. In most of these groups of rats, storage of retinol in parenchymal cells was proportional to the liver store of retinol, and less than 10% of total retinol in the liver could be recovered in the parenchymal cells. The only exception was parenchymal cells isolated from vitamin A-deficient rats. In rats containing 5 nmol retinol/g liver, about 16% of total retinol could be recovered in parenchymal cells, while in rats with only 1 nmol retinol/g liver, about 40% of total retinol could be recovered in parenchymal cells. 4. These results indicate that parenchymal cells played a minor role in liver storage of retinol, and that stellate cells stored more than 90% of liver retinol in most instances. Only in rats with a low retinol status did the percentage of retinol in parenchymal cells increase.
Aging↗
Changes in hepatic parenchymal and nonparenchymal cell vitamin A content during vitamin A depletion in the rat.
Levels of total, unesterified and esterified retinol were determined in liver, liver parenchymal cells (PC) and liver nonparenchymal cells (NPC) during vitamin A depletion in rats. Liver vitamin A levels decreased from 113 to 4 micrograms over a 97-d experimental period; plasma retinol concentrations did not change significantly during this time. Initially, greater than 90% of hepatic vitamin A was in the esterified form and most (93%) was localized in NPC. During vitamin A depletion, there were significant declines in retinyl ester content of both PC and NPC, but unesterified retinol levels were not significantly affected. Plasma retinol concentrations were significantly correlated with unesterified retinol mass in PC and NPC, but not with retinyl ester mass. Although 94% of the liver's negative vitamin A balance was due to changes in NPC retinyl ester levels, the fractional rate of retinyl ester loss from PC and NPC was almost identical. Since unesterified retinol levels in plasma, PC and NPC appeared to be conserved even when liver retinyl ester stores were virtually depleted, and since the retinol utilization rate was apparently not decreasing during this stage of vitamin A depletion, these data support the hypotheses that homeostatic mechanisms controlling the three pools of unesterified retinol are linked, and that vitamin A utilization rate is maintained as long as unesterified retinol levels in plasma, PC and NPC are normal.
Animals↗
High-dose retinol in children with acute myelogenous leukemia in remission.
In a single-institution study, 23 consecutive children with acute myeloid leukemia (AML) have been treated with a protocol including doxorubicin, cytarabine and 6-thioguanine as induction therapy, followed by four courses of high-dose cytarabine as consolidation. Total duration of chemotherapy was 6-8 months from diagnosis. 21 out of the 23 children achieved complete remission. During remission, the children received 52 mumol (50,000 I.U.) retinol as retinyl palmitate per square meter daily. 14 of the 21 children are still in their first remission with a mean observation time of 36 months. In our study retinyl ester given in doses up to 30 times the recommended daily allowances has not caused any clinical or biochemical side effect for up to 4 yr of therapy.
Adolescent↗
Fats and diet.
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Cardiovascular Diseases↗
Feeding of partially hydrogenated fish oils to rats in comparison with partially hydrogenated soybean oil and refined rapeseed oil: a combined chronic oral toxicity and carcinogenicity study with in utero phase.
Partially hydrogenated fish oils (PHFO) have been widely used in human food products for many years, particularly in Europe, North and South America and in South Africa. Animal studies, mainly with rapeseed oil, suggested that erucic acid might be responsible for morphological changes in the myocardium. It was suggested that other members of the docosenoic (22:1) family of fatty acids might produce similar effects to those ascribed to erucic acid. Certain PHFO can contain relatively high levels of these other isomers. Thus it was decided to evaluate PHFO of differing 22:1 levels in comparison with partially hydrogenated soybean oil (PHSBO) and refined rapeseed oil (LEAR) in a rat life span study, preceded by a breeding period in which the experimental lipids were fed to male and female parents. Two commercially produced PHFO were selected to represent the lower (PHFO-L) and upper (PHFO-U) range of 22:1 contents, 4.3 and 13.8%, respectively. A third test oil was prepared from a 50:50 blend of these (PHFO-M) to provide and intermediary 22:1 level. The control PHSBO and LEAR contained 0 and 1.0% 22:1, respectively. These experimental oils were included in semi-purified diets at 8 and 16%, respectively, in the breeding and life span periods of the study, together with 4% of oil mixtures providing essential fatty acids (EFA). Specific pathogen free (SPF). Wistar weanling rats, 200 of each sex, provided the subjects for the breeding period. Sufficient numbers of offspring were obtained in suitable condition from each treatment group to allow selection of a total of 555 weanlings for allocation to the five dietary treatments of the life span period of the study. For the life span period of the study, which was terminated after 107 to 110 weeks of treatment, 50 subjects were allocated to each of the PHSBO, PHFO-L and PHFO-U dietary groups, and 50 males to each of the LEAR and PHFO-M groups. The remaining subjects were allocated to sub-groups for sacrifice four days or 26 weeks after introduction of the life span period diets. All life span group subjects were weighed and had their food intakes recorded, and were subjected to clinical examination, routinely. At designated stages, ophthalmoscopic examination of all subjects was carried out, and samples of blood and urine were obtained from sub-groups for laboratory analysis. All decedent and terminated life span group subjects were subjected to post mortem examination, with weighing of 16 organs.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Liver takes up retinol-binding protein from plasma.
Retinol is transported in plasma bound to a specific transport protein, retinol-binding protein. We prepared 125I-tyramine cellobiose-labeled rat retinol-binding protein and studied its tissue uptake 1, 5, and 24 h after intravenous injection into rats. The liver was the organ containing most radioactivity at all time points studied. After 5 and 24 h, 30 and 22% of the injected dose were recovered in liver, respectively. After separating the liver into parenchymal and nonparenchymal cells in the 5-h group, we found that both cell fractions contained approximately the same amount of radioactivity (per gram of liver). Most of the retinol-binding protein radioactivity in the nonparenchymal cell fraction was in the stellate cells. The implication of these results for a possible transfer mechanism for retinol between parenchymal and stellate cells is discussed.
Animals↗
The relationship between autophagy and the intracellular degradation of asialoglycoproteins in cultured rat hepatocytes.
The relationship between autophagy and the intracellular distribution of endocytosed asialoorosomucoid was studied in cultured rat hepatocytes. Overt autophagy was induced by shifting the cells to a minimal salt medium. Incubation in minimal salt medium led to the formation of buoyant lysosomes at the expense of denser lysosomes manifested as a dual distribution of these organelles in Nycodenz gradients. Asialoorosomucoid was labeled with 125I-tyramine cellobiose. The labeled degradation products formed from this ligand are trapped at the site of degradation and may therefore serve as markers for the subgroup of lysosomes involved in the degradation. In control cells the degradation of the ligand was initiated in a light prelysosomal compartment and continued in denser lysosomes. In cells with high autophagic activity, the degradation of labeled asialoorosomucoid took place exclusively in a buoyant group of lysosomes. These results suggest that degradation of endocytosed ligand takes place in the same secondary lysosomes as substrate sequestered by autophagic mechanisms. These light lysosomes represent a subgroup of active lysosomes which are gradually recruited from dense bodies. Data are also presented that indicate that insulin may prevent the change in buoyant density brought about by incubation in deficient medium.
Animals↗
Fatty-acid chain elongation in rat small intestine.
Microsomal fractions from rat small intestine contain a fatty-acid chain-elongation activity. Cofactor requirements are similar to those of the liver microsomal system, but substrate specificity is different. The polyunsaturated arachidonic and timnodonic acids were elongated at very low rates. These results suggest that the relative contents of specific chain-elongation enzymes are different in liver and small intestine.
Animals↗
Metabolism of retinol in the intestine and liver.
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Acyltransferases↗
All-trans-retinoic acid inhibits retinol esterification by acyl-CoA: retinol acyltransferase (EC 2.3.1.76) from rat and human small intestinal mucosa.
1. Formation of retinyl esters catalyzed by acyl-CoA:retinol acyltransferase (ARAT; retinol fatty-acyltransferase; EC 2.3.1.76) from intestinal mucosa has been studied in vitro in the presence of all-trans-retinoic acid. 2. The incubation system contained microsomal preparations from the tissue tested, radioactive retinol and palmitoyl-CoA. The product formed was separated from the substrates by chromatography on alumina columns. 3. All-trans-retinoic acid inhibited ARAT both from rat and human intestinal mucosa. 4. Inhibition occurred instantly. At a concentration of retinol of 80 microM, a 50% inhibition was obtained with 50 microM-retinoic acid. 5. The inhibition of ARAT by retinoic acid may be of importance for normal retinol absorption in patients receiving retinoid therapy.
Acyltransferases↗
Effect of alcohol consumption on serum concentration of 25-hydroxyvitamin D3, retinol, and retinol-binding protein.
The effect of chronic alcohol consumption on the concentration of 25-hydroxyvitamin D3, total retinol, and retinol-binding protein in serum was studied in chronic alcoholics (n = 12) and controls (n = 19). Ethanol intake during the last year was 178 +/- 116 and 3.7 +/- 4.5 g/day, respectively (p less than 0.002). Of the alcoholics, 58% had a concentration of 25-hydroxyvitamin D3 below lower limit of reference (20 ng/ml). Estimated dietary intake of vitamin D last year was not significantly different for the alcoholics and controls. Concentration of calcium in serum was significantly lower in alcoholics than in controls (p less than 0.05). The serum concentration of retinol and retinol-binding protein was similar in the two groups. These observations may be of relevance for some of the clinical findings related to bone disease among heavy alcohol consumers.
Adult↗
Low and high risk coronary patients discriminated by blood platelet fatty acid composition.
The distribution of 11 long-chain fatty acids in platelet phospholipids were subjected to multivariate statistical analysis with groups of high and low risk coronary patients and controls. The alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) had significant explanatory power between the groups. As has been anticipated from studies in Eskimos, the EPA fraction was low in coronary patients. It was lower in high risk patients than in low risk patients, and lower in patients below rather than above, 60 years of age. Young high risk patients had 1.2 +/- 0.2% (Mean, SE) EPA against 1.8 +/- 0.2% in young controls, (p = 0.035). Old low risk patients had the highest EPA and also the highest DHA, 2.9 +/- 0.3% against 2.3 +/- 0.2% in controls. The ALA was low in low risk patients. Patients with low platelet EPA and high serum cholesterol should be included in trials with EPA rich diets.
Aged↗