[Treatment of hypercholesterolemia in adults. An action plan].
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Adult↗
Biomedical subjects
C A Drevon
Publications and source records attributed to C A Drevon.
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↗
Eicosapentaenoic acid inhibits cholesterol esterification in cultured parenchymal cells and isolated microsomes from rat liver.
The effects of eicosapentaenoic acid on synthesis and secretion of cholesterol and cholesterol ester by cultured rat hepatocytes were studied. In the presence of eicosapentaenoic acid cellular cholesterol esterification was decreased by 50-75% compared to oleic acid as measured by radioactive precursors and mass. Secretion of cholesterol ester was reduced by 50-60% in the presence of eicosapentaenoic acid as evaluated by radiolabeled fatty acids, mevalonolactone, and mass measurement. Oleic, palmitic, and stearic acid increased, whereas eicosapentaenoic and docosahexaenoic acid decreased synthesis and secretion of cholesterol ester as compared to a fatty acid-free control. Cellular and secreted free cholesterol were unaffected by eicosapentaenoic acid in comparison with oleic acid. The reduced cholesterol esterification was observed within 1 h and lasted for at least 20 h. Eicosapentaenoic acid caused lower cholesterol esterification than oleic acid in the concentration range 0.2-1.0 mM fatty acid and reduced the stimulatory effect of oleic acid on cholesterol ester formation. Cholesterol esterification and release of cholesterol ester were markedly increased by 25-hydroxycholesterol in the presence of eicosapentaenoic acid as well as oleic acid. Experiments with liver microsomes revealed that radioactive eicosapentaenoic acid and eicosapentaenoyl-CoA were poorer substrates (7-30%) for cholesterol esterification than oleic acid and oleoyl-CoA. Reduced formation of cholesterol ester was also observed when eicosapentaenoyl-CoA was given together with labeled oleoyl-CoA, whereas palmitoyl-CoA, stearoyl-CoA, linolenoyl-CoA, and arachidonoyl-CoA had no inhibitory effect. In conclusion, eicosapentaenoic acid reduced cellular cholesterol esterification by inhibiting the activity of acyl-CoA:cholesterol acyltransferase. The lowered cholesterol esterification caused by eicosapentaenoic acid secondly decreased secretion of very low density lipoprotein cholesterol ester.
Animals↗
A three-year prospective study of rearrests for driving under influence of alcohol or drugs.
Fifty drunken drivers and 50 drivers with high blood drug concentrations arrested during the first four months of 1983 were selected for a study of rearrests for driving under influence of alcohol or drugs. Of the drugged drivers selected, 32 had been driving with high blood concentrations of diazepam (greater than 1.0 microM). 50% of these drivers were rearrested during the subsequent three years. The rearrest rate was low (6%) among those who had been driving with high blood concentrations of amphetamine (greater than 2.0 microM) or THC (greater than 0.010 microM). Among the drunken drivers arrested (BAC greater than 0.05%), the rearrest rate was 20%. The drivers were mostly rearrested for driving under the influence of alcohol.
Adult↗
Effect of dietary supplementation with n-3 fatty acids on clinical manifestations of psoriasis.
In a double-blind, block randomized study we investigated the effect of dietary supplementation with eicosapentaenoic acid in patients with psoriasis. The experimental group received 10 g of fish oil daily containing approximately 1.8 g eicosapentaenoic acid, while the controls were given an isoenergetic amount of olive oil. We found no significant change in the clinical manifestations of psoriasis in either group after 8 weeks of treatment. In the experimental group, the amount of n-3 fatty acids in serum phospholipids was significantly increased at the end of trial as compared to pre-treatment values, whereas the level of n-6 fatty acids was decreased.
Adolescent↗
Calcium status and calcium-regulating hormones in alcoholics.
To elucidate effects of chronic ethanol consumption on clinical chemical parameters reflecting overall calcium homeostasis 34 hospitalized male alcoholics and 35 age-matched controls were studied during the winter season. Serum concentrations of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 were reduced by 28% (p less than 0.01) and 24% (p less than 0.02) among the alcoholics as compared to the controls, respectively. Dietary intake of vitamin D3 did not differ significantly between the groups. The calcium level was below lower limit of reference in nine alcoholics (26%). Serum concentrations of parathyroid hormone and phosphorus were within normal ranges in both groups, and no differences were observed in levels of magnesium, vitamin D-binding protein, calcitonin, or alkaline phosphatase. In conclusion, it is possible that the activities of enzymes crucial in vitamin D3 metabolism may be altered in alcoholics.
Adult↗
Reduced IgG Fc-receptor-mediated phagocytosis in human monocytes isolated from alcoholics.
Blood monocytes (MC) were isolated from alcoholics and from age-matched controls. Phagocytosis mediated by the IgG Fc-receptor (Fc-R) was assessed in the MC immediately after isolation by using IgG-opsonized sheep erythrocytes as test particles. Experiments were also performed after preincubating the MC in medium containing 10% autologous serum with or without ethanol (80 mM) in vitro at 37 degrees C for 15 min, and with or without ethanol (80 mM) present during the internalization assay in vitro (37 degrees C for 60 min). MC from alcoholics exhibited lower phagocytic capacity via the Fc-R than MC from healthy controls, approximately 50% versus 70% phagocytosing cells. Preincubation of the MC in medium containing 10% autologous serum with 80 mM ethanol, reduced the percentage of phagocytosing MC from controls to 55%, whereas no further reduction occurred in cells from alcoholics. When present during the assays of Fc-R function, ethanol decreased MC phagocytosis of IgG-coated particles significantly in both test groups, to about 30% phagocytosing cells. Blood samples disclosed increased serum levels of markers of liver dysfunction, immunoglobulins, increased sedimentation rate, and white blood cell counts among the alcoholics, while their serum levels of 1,25-dihydroxyvitamin D3 were reduced.
Adult↗
Some aspects of antioxidant status in blood from alcoholics.
The effect of ethanol consumption on serum concentration of alpha-tocopherol, erythrocyte activities of superoxide dismutase, glutathione peroxidase, and catalase were studied in 34 male alcoholics and 35 age-matched controls. Serum concentration of alpha-tocopherol was 30% lower in the alcoholics as compared to the controls (p less than 0.001). No significant difference was found in erythrocyte activities of Cu-Zn-containing superoxide dismutase, glutathione peroxidase, or catalase between the groups. Of the 12 alcoholics with subnormal serum alpha-tocopherol, 50% had concomitant neurological clinical scores and cerebellar atrophy, and their neurological scores were significantly higher (82%) than for alcoholics with normal alpha-tocopherol levels (p less than 0.03). However, no significant correlation was observed between levels of alpha-tocopherol and neurological clinical scores or cerebellar atrophy. When entering the study, alcoholics and controls were each randomized into two separate groups, receiving vitamin E supplementation (100 mg/day) or placebo capsules for 10 days, respectively. In the four subgroups, alpha-tocopherol levels increased only in alcoholics receiving vitamin E supplementation (23%) (p less than 0.001). The reduced serum levels of alpha-tocopherol in alcoholics may be normalized by vitamin E supplementation.
Adult↗
Diminished serum concentration of vitamin E in alcoholics.
The effect of heavy alcohol consumption on serum concentrations of vitamin E (alpha-tocopherol) and selenium was studied in 13 alcoholics and 19 control subjects. Ethanol intake during the year previous to the study was in the range from 22 to 354 g/day and from 0 to 16 g/day among the alcoholics and controls, respectively. Of the 13 alcoholics, 6 had a serum concentration of alpha-tocopherol below the lower limit of reference (14 mumol/l) and mean serum concentration of alpha-tocopherol was reduced by 37% as compared to controls (p less than 0.002). Estimated dietary intake of alpha-tocopherol during the year previous to the study was approximately 40% lower for the alcoholics (p less than 0.05). During hard-drinking periods the alcoholics had a markedly reduced intake of alpha-tocopherol as compared to moderate-drinking and abstinent periods. Mean serum concentration of selenium was significantly reduced in the alcoholics (1.2 +/- 0.3 mumol/l) as compared to the controls (1.6 +/- 0.2 mumol/l) (p less than 0.002). The reduced serum levels of alpha-tocopherol and selenium may influence the maintenance of normal cell structure and function, and contribute to development of diseases frequently observed in alcoholics.
Adult↗
Eicosapentaenoic acid reduces hepatic synthesis and secretion of triacylglycerol by decreasing the activity of acyl-coenzyme A:1,2-diacylglycerol acyltransferase.
The mechanism for the reduced hepatic production of triacylglycerol in the presence of eicosapentaenoic acid was explored in short-term experiments using cultured parenchymal cells and microsomes from rat liver. Oleic, palmitic, stearic, and linoleic acids were the most potent stimulators of triacyl[3H]glycerol synthesis and secretion by hepatocytes, whereas erucic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic, and eicosapentaenoic acids (in decreasing order) were less stimulatory. There was a linear correlation (r = 0.85, P less than 0.01) between synthesis and secretion of triacyl[3H]glycerol for the fatty acids examined. The extreme and opposite effects of eicosapentaenoic and oleic acids on triacylglycerol metabolism were studied in more detail. With increasing number of free fatty acid molecules bound per molecule of albumin, the rate of synthesis and secretion of triacyl[3H]glycerol increased, most markedly for oleic acid. Cellular uptake of the two fatty acids was similar, but more free eicosapentaenoic acid accumulated intracellularly. Eicosapentaenoic acid caused higher incorporation of [3H]water into phospholipid and lower incorporation into triacylglycerol and cholesteryl ester as compared to oleic acid. No difference was observed between the fatty acids on incorporation into cellular free fatty acids, monoacylglycerol and diacylglycerol. The amount of some 16- and 18-carbon fatty acids in triacylglycerol was significantly higher in the presence of oleic acid compared with eicosapentaenoic acid. Rat liver microsomes in the presence of added 1,2-dioleoyl-glycerol incorporated eicosapentaenoic acid and eicosapentaenoyl-CoA into triacylglycerol to a lesser extent than oleic acid and its CoA derivative. Decreased formation of triacylglycerol was also observed when eicosapentaenoyl-CoA was given together with oleoyl-CoA, whereas palmitoyl-CoA, stearoyl-CoA, linoleoyl-CoA, linolenoyl-CoA, and arachi-donoyl-CoA had no inhibitory effect. In conclusion, inhibition of acyl-CoA:1,2-diacylglycerol O-acyltransferase (EC 2.3.1.20) by eicosapentaenoic acid may be important for reduced synthesis and secretion of triacylglycerol from the liver.
Acyl Coenzyme A↗
Fats and diet.
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Cardiovascular Diseases↗
Acute and chronic effects of ethanol on secretion of alpha-tocopherol from primary cultures of rat hepatocytes.
Primary cultures of rat hepatocytes were used to study the effect of acute and chronic ethanol exposure on alpha-tocopherol content in cells and media. Cells treated acutely with 60 mM ethanol secreted 74.5 +/- 18.0% (P less than 0.05), and their cellular alpha-tocopherol content was 85.7 +/- 15.4% (not significant) of controls after 20 h incubation. At this time total recovery of alpha-tocopherol was significantly reduced in ethanol-exposed cells (43.1 +/- 8.4%) as compared to control cells (52.8 +/- 5.0%, P less than 0.05). Hepatocytes isolated from chronic ethanol-fed rats (35% of total energy intake as ethanol for 5 weeks) secreted 41.9 +/- 12.7% less alpha-tocopherol than did cells of pair-fed controls during 20 h incubation (P less than 0.05). The amount of alpha-tocopherol secreted was then 15.6 +/- 4.2 and 19.8 +/- 3.8% of cell-associated alpha-tocopherol at start of incubation for chronic ethanol-fed and control rats, respectively (P less than 0.05). When 60 mM ethanol was added to the incubation medium, hepatocytes of control rats secreted significantly less alpha-tocopherol (about 30%, P less than 0.05), whereas alpha-tocopherol secretion was not significantly reduced in hepatocytes of chronic ethanol-fed rats. We conclude that both acute and chronic ethanol exposure reduce alpha-tocopherol secretion from rat hepatocytes.
Animals↗
Secretion of alpha-tocopherol from cultured rat hepatocytes.
Primary cultures of rat hepatocytes and rat liver perfusions were used to study hepatic secretion of alpha-tocopherol. The secretion of alpha-tocopherol from hepatocytes in culture was linear with time for 4 h. Ultracentrifugation of the medium revealed that 89.4 +/- 2.1% of alpha-tocopherol secreted during 4 h incubation was associated with the very-low density lipoprotein fraction (VLDL, d less than 1.006 g/ml). Oleic acid had no significant effect on the secretory rate of alpha-tocopherol, whereas eicosapentaenoic acid reduced the amount of alpha-tocopherol secreted to 48.4 +/- 12.7% of the control value after 20 h incubation (P less than 0.01). Monensin, a known inhibitor of VLDL secretion, reduced the secretion of alpha-tocopherol to 14.1 +/- 4.3% of the control value (P less than 0.02). Colchicine and chloroquine inhibited the secretion of alpha-tocopherol in the same order of magnitude as monensin. Hepatic perfusion after intravenous injection of in vivo labeled alpha-[3H]tocopherol lymph, showed that about 75% of the secreted radioactivity was in the VLDL fraction. From these results we conclude that most alpha-tocopherol is secreted from the liver associated with nascent VLDL in rats.
Animals↗
Calcium-antagonists inhibit secretion of very-low-density lipoprotein from cultured rat hepatocytes.
The effects of different calcium-antagonists on secretion of very-low-density lipoprotein (VLDL) from cultured rat hepatocytes were examined. Verapamil (an inhibitor of voltage-dependent calcium channels) and EGTA (a calcium chelator) decreased VLDL-triacylglycerol secretion in a concentration-dependent manner, with maximum inhibition (about 90%) at 0.2 mM-verapamil and 5 mM-EGTA. Inorganic calcium-antagonists such as lanthanum, nickel, cobalt and manganese decreased secretion of VLDL-triacylglycerol by 55-95%, whereas the calcium-agonist barium did not affect secretion. Inhibition of VLDL-triacylglycerol secretion appeared within 30 min, without inhibition of triacylglycerol synthesis. Pulse-chase experiments revealed that verapamil and cobalt inhibited the secretory pathway itself. Cobalt showed a concentration-dependent inhibition of VLDL-triacylglycerol secretion, with maximal effect at 8 mM. Although inhibition by cobalt was not completely reversible, Trypan Blue exclusion and lactate dehydrogenase leakage indicated that the hepatocytes were not injured by cobalt or any of the other calcium-antagonists tested. Inhibition of protein synthesis by cycloheximide did not affect triacylglycerol secretion (up to 2 h), and the observed effects were therefore probably not due to impaired production of apolipoproteins. Taken together, these results suggest that calcium is important for secretion of VLDL particles.
Animals↗
Inhibition of very-low-density lipoprotein secretion by chloroquine, verapamil and monensin takes place in the Golgi complex.
The effects of chloroquine, verapamil and monensin on secretion of very-low-density lipoproteins (VLDLs) were studied in cultured rat hepatocytes. Maximum inhibition of VLDL-triacylglycerol secretion by 50-90% of control was reached at 200 microM chloroquine, 200 microM verapamil and 5 microM monensin, whereas no effect on cellular triacylglycerol synthesis was observed. The inhibition could be seen within 15 min and was reversible after washout of the drugs. Chloroquine and verapamil inhibited both cellular protein synthesis and protein secretion, whereas monensin reduced protein secretion without any effect on protein synthesis. Control experiments with cycloheximide revealed that intact protein synthesis was not necessary for secretion of VLDL-triacylglycerol during 2 h. Electron micrographs of cells treated with chloroquine, verapamil or monensin showed swollen Golgi cisternae containing VLDL-like particles. By morphometry, a more than 2-fold increase in volume fractions and size indices of Golgi complexes and secondary lysosomes was observed, except that monensin had no significant effect on these parameters of secondary lysosomes. These results suggest that the inhibition of VLDL secretion by chloroquine, verapamil and monensin which takes place in the Golgi complex might be due to disruption of trans-membrane proton gradients. An increase in pH of acidic Golgi vesicles may cause swelling and disturb sorting and membrane flow through this organelle.
Animals↗
Serum half-life, distribution, hepatic uptake and biliary excretion of alpha-tocopherol in rats.
The serum clearance of alpha-[3H]tocopherol has been studied after intravenous injection of intestinal lymph labeled in vivo with radioactive alpha-tocopherol. The half-life of the injected alpha-[3H]tocopherol was approx. 12 min. Fractionation of plasma by ultracentrifugation 10 min after injection of lymph showed that 91% of the radioactive alpha-tocopherol remaining in plasma was located in chylomicrons (d less than 1.006 g/ml) and 7.8% in high-density lipoproteins (HDL, 1.05 less than d less than 1.21 g/ml). 2 h after administration of alpha-tocopherol, about 35% of the radioactivity recovered in plasma was associated with chylomicrons and approx. 51% with HDLs. alpha-[3H]Tocopherol was initially taken up by the liver, which contained more than 50% of the injected radioactivity after 45-60 min. Separation of parenchymal and nonparenchymal cells demonstrated a preferential uptake of alpha-[3H]tocopherol by the parenchymal liver cells. After 24 h about 11% of the injected dose was recovered in the liver. Considering whole organs the liver, adipose tissue and skeletal muscle had the highest content of radioactivity after 24 h. Furthermore, about 14% of the administered dose was recovered in bile during 24 h draining.
Adipose Tissue↗
Reduced hepatic alpha-tocopherol content after long-term administration of ethanol to rats.
We have studied the effects of long-term administration of ethanol on the distribution and pharmacokinetics of alpha-tocopherol. In rats fed ethanol (35% of total energy) for 5-6 weeks concentration of alpha-tocopherol in whole liver was reduced by 25% as compared to the pair-fed controls (P less than 0.003). This reduction was significant in the parenchymal cells (28%, P less than 0.004), whereas no significant difference was observed for the nonparenchymal cells. Mitochondrial alpha-tocopherol content was reduced by 55% in the ethanol-treated rats as compared to the controls (P less than 0.002), whereas no significant difference was observed in microsomes, light mitochondria or cytosol. The serum levels of alpha-tocopherol showed no significant difference between the groups. When in vivo labeled chylomicron alpha-[3H]tocopherol was injected intravenously to anesthetized rats, we found a significant increase in serum half-life of alpha-tocopherol in the ethanol-treated group as compared to the controls (P less than 0.025). Hepatic alpha-[3H]tocopherol content was similar in the two groups 24 h after injection.
Animals↗
[Essential fatty acids. Function and clinical aspects].
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Fatty Acids, Essential↗