| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Metabolic variables of cholesterol during squalene feeding in humans: comparison with cholestyramine treatment Strandberg, T. E., R. S. Tilvis, et al. (1990), J Lipid Res 31(9): 1637-43. Abstract: Squalene, a key intermediate of cholesterol synthesis, is present especially in olive oil. Regulation of cholesterol metabolism by dietary squalene in man is unknown, even though olive oil users in Mediterranean areas have low serum cholesterol levels. We have investigated absorption and serum levels of squalene and cholesterol and cholesterol synthesis with the sterol balance technique and serum levels of cholesterol precursors in humans during squalene feeding (900 mg/d for 7-30 days). The results were compared with those during cholestyramine treatment. Fecal analysis suggested that about 60% of dietary squalene was absorbed. Serum squalene levels were increased 17 times, but serum triglyceride and cholesterol contents were unchanged. The squalene feeding significantly (P less than 0.05) increased serum levels of free (1.7-2.3 times) and esterified (1.9-2.4 times) methyl sterol contents, while elevations of free and esterified delta 8-cholesterol and lathosterol levels were inconsistent. Cholestyramine treatment modestly augmented free methyl sterol levels (1.3-1.7 times), less consistently than those of esterified ones, while, in contrast to the squalene feeding, serum contents of free and esterified delta 8-cholesterol and lathosterol were dramatically increased (3.3-8 times). Neither of the treatments significantly affected serum plant sterol and cholestanol levels. The squalene feeding had no consistent effect on absorption efficiency of cholesterol, but significantly increased (paired t-test, P less than 0.05) the fecal excretions of cholesterol and its nonpolar derivatives coprostanol, epicoprostanol, and coprostanone (655 +/- 83 SE to 856 +/- 146 mg/d) and bile acids (212 +/- 24 to 255 +/- 24 mg/d), indicating an increase of cholesterol synthesis by about 50%. We suggest that a substantial amount of dietary squalene is absorbed and converted to cholesterol in humans, but this squalene-induced increase in synthesis is not associated with consistent increases of serum cholesterol levels. The clearly increased serum contents of esterified methyl sterols may reflect stimulated tissue acyl CoA: cholesterol acyltransferase (ACAT, EC 2.3.1.26) activity during squalene feeding as these sterols are not esterified in serum. |
| Metabolism and effect on cholesterol metabolism of 3 alpha-hydroxy-7-hydroxyimino-5 beta-cholanoic acid in hamsters Miki, S., M. Une, et al. (1990), J Pharmacobiodyn 13(9): 558-64. Abstract: The metabolic fate of a bile acid analog, 3 alpha-hydroxy-7-hydroxyimino-5 beta-cholanoic acid, was studied in hamsters. This compound was absorbed rapidly from the intestine and secreted into the bile as either taurine- or glycine-conjugates, at the rate similar to that of chenodeoxycholic acid. The ratio of glycine to taurine conjugates for this bile acid analog, 0.2, was much smaller than that for chenodeoxycholic acid, 2.0. After oral administration of a single dose of the labeled analog to intact hamsters, radioactivity was recovered in faces but not in urine. A major metabolite found in the feces was lithocholic acid (60%), whereas unchanged material was present only in a trace amount (2.4%). After the hamsters were fed chow supplemented with 0.075% of this bile acid analog for 21 d, analysis of the gallbladder bile acids revealed that the administered compound accounted for only 1.6% of total bile acids. The biliary bile acid composition was similar to that of chenodeoxycholic acid fed group. In the strain of hamster studied, feeding of the bile acid analog decreased cholesterol absorption significantly (19% decrease, p less than 0.05), and tended to reduce serum and liver cholesterol concentrations. |
| Metabolism and turnover of cell surface-associated heparan sulfate proteoglycan and chondroitin sulfate proteoglycan in normal and cholesterol-enriched macrophages Owens, R. T. and W. D. Wagner (1991), Arterioscler Thromb 11(6): 1752-8. Abstract: Analysis of sulfur-35-labeled proteoglycans indicated that cholesterol-enriched pigeon peritoneal macrophages synthesized 42% more 35S-labeled proteoglycan when compared with control macrophages during a 24-hour incubation. Proteoglycan turnover was subsequently studied in radiolabeled macrophage cultures after a 1-, 3-, 6-, 12-, or 24-hour chase with fresh media. During the chase, intracellular proteoglycan disappeared rapidly, whereas there was a small accumulation of 35S-labeled proteoglycan in the media that plateaued at about 6 hours and remained relatively constant thereafter. Pericellular heparan sulfate proteoglycan and chondroitin sulfate proteoglycan disappeared throughout the chase and did not appear to accumulate in the media or in the intracellular compartment. The rapid disappearance of intracellular proteoglycans along with the relative lack in metabolism of media proteoglycans indicated that the majority of pericellular proteoglycans were metabolized via an intracellular degradative pathway. Kinetic analysis of pericellular proteoglycans revealed the presence of a single pool of heparan sulfate proteoglycan (half-life t1/2 = 6.9 hours) and a single pool of chondroitin sulfate proteoglycan (t1/2 = 11.5 hours) in control macrophage cultures. Cholesterol-enriched macrophage cultures also contained a single pool of pericellular heparan sulfate proteoglycan (t1/2 = 7.3 hours) but contained two pools of chondroitin sulfate proteoglycan (t1/2 = 0.8 hour and 25.9 hours). |
| Metabolism in vitro of cholesterol and 25-hydroxycholesterol by the larval prothoracic glands of Manduca sexta Warren, J. T. and L. I. Gilbert (1996), Insect Biochem Mol Biol 26(8-9): 917-29. Abstract: The prothoracic glands in vitro convert 25-hydroxycholesterol (25C) to 25-hydroxy-7-dehydrocholesterol (7d25C) and to ecdysteroids at a greater rate than cholesterol (C) is converted to ecdysteroids via 7-dehydrocholesterol (7dC). Mediated via a cytochrome P450 most probably located in the endoplasmic reticulum (ER), both intact and extensively homogenized prothoracic glands, as well as crude subcellular fractions, were able to 7,8-dehydrogenate 25C to 7d25C eight-fold more efficiently than they could convert C to 7dC. However, less than a two-fold difference was observed in the subsequent monooxygenase mediated conversion of these two intermediates formed in situ into ecdysteroids, mainly ecdysone (E) and 2-deoxyecdysone (2dE) and/or their 3-dehydroderivatives. When 7dC, and particularly 7d25C, were made directly available to these tissue preparations, their conversion to ecdysteroids greatly exceeded that of the in situ conversion of either C or 25C, via 7dC or 7d25C, respectively. Indeed, there was an eight-fold increase in the VMAX for 25C dehydrogenation by homogenized glands relative to the dehydrogenation of C. Most important, however, was the 1000-fold increase in the VMAX observed for the direct production of E from emulsified 7d25C by gland homogenates relative to E production from 25C via 7d25C synthesized in situ. Thus, it is apparent that even after the rapid and efficient conversion of 25C to 7d25C within the ER, the subsequent rate of conversion of this intermediate to E is greatly retarded relative to that observed following the direct incubation of emulsified 7d25C with gland homogenates. These differential kinetics of direct and indirect 7d25C incorporation into E are interpreted as evidence for the existence of a barrier to the efficient translocation of the delta 5,7-sterol intermediates from the ER to another site where the subsequent, uncharacterized initial conversions leading to ecdysteroids take place. On the basis of studies on mammalian adrenal cortical steroidogenesis, this site is postulated to be the inner membrane/matrix of the mitochondria. The present data support the hypothesis that the translocation of both 7dC and 7d25C, first from the site of their probable synthesis within the ER membranes, next through the cytosol to the outer mitochondrial membrane, and then across the intramitochondrial aqueous space to the inner membrane/matrix compartment, may be analogous to the translocation in the adrenal cortex of ER-derived C, first to the plasma membrane and/or to the outer mitochondrial membrane and then to the inner mitochondrial membrane/matrix for P450scc-mediated conversion into pregnenolone. |
| Metabolism of 3Hfarnesol to cholesterol and cholesterogenic intermediates in the living rat eye Fliesler, S. J. and R. K. Keller (1995), Biochem Biophys Res Commun 210(3): 695-702. Abstract: Adult rats were injected intravitreally with all-trans 1-3Hfarnesol, with or without co-injection of the squalene epoxidase inhibitor NB-598. Retinas were isolated 16 h later and their lipids were extracted, saponified, and analyzed by radio-HPLC. Most (> or = 90%) of the nonsaponifiable radioactivity was recovered as unmetabolized 3Hfarnesol; however, about 6-8% of the radioactivity in control retinas exhibited the chromatographic behavior of sterols, including cholesterol. Unlike the controls, the NB-598-treated retinas exhibited substantial accumulation of both 3Hsqualene and squalene mass. Calculations indicate that most of the squalene mass was derived from metabolism of endogenous precursors, with an in vivo biosynthetic rate of 46 +/- 17.5 pmol/retina/h. Retinas from eyes injected with all-trans 1-3Hgeranylgeraniol yielded only the unmetabolized precursor in the nonsaponifiable extracts. These results suggest that farnesol can be "activated" in vivo (presumably to the corresponding allylic pyrophosphate) in the retina and subsequently metabolized to sterols and sterol precursors. |
| Metabolism of 7 beta-alkyl chenodeoxycholic acid analogs and their effect on cholesterol metabolism in hamsters Une, M., K. Yamanaga, et al. (1990), J Lipid Res 31(6): 1015-21. Abstract: The metabolism of 7-ethyl- and 7-propyl-chenodeoxycholic acids was studied in hamsters. Both bile acid analogs were absorbed efficiently by the intestine and secreted into the bile at rates similar to those of chenodeoxycholic acid. After intraduodenal administration into bile fistula hamsters, the 7-alkyl analogs were present in bile as the glycine and taurine conjugates. The glycine/taurine ratios were: chenodeoxycholic acid, 1.9; 7-ethyl analog, 0.3; and 7-propyl analog, 0.2. After oral administration, during a 21-day feeding experiment, the 14C-labeled analogs were recovered quantitatively in the feces. Chenodeoxycholic acid was largely 7-dehydroxylated to lithocholic acid in the intestinal tract. In contrast, the 7 alpha-hydroxy group of the 7-alkyl bile acids was completely resistant to bacterial action. 7-Ethyl-chenodeoxycholic acid was transformed in part to a compound tentatively identified as 7 alpha-hydroxy-3-oxo- 7 beta-ethyl-5 beta-cholanoic acid while 7-propyl-chenodeoxycholic acid was excreted unchanged. In the hamsters used, the 7-alkyl bile acid analogs did not inhibit the bacterial dehydroxylation of chenodeoxycholic acid. At the end of the 21-day feeding period, analysis of the gallbladder bile showed that 7-methyl-, 7-ethyl-, and 7-propyl-chenodeoxycholic acids accounted for 38, 31, and 12% of total bile acids, respectively. The 7-alkyl bile acids decreased cholesterol absorption; the 7-propyl analog caused significant decrease in serum and liver cholesterol concentration. These experiments demonstrate that the 7-ethyl- and 7-propyl chenodeoxycholic acids, just like the 7-methyl-analog, are absorbed by the intestine and participate in the enterohepatic circulation.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Metabolism of a cholesterol-rich microemulsion (LDE) in patients with multiple myeloma and a preliminary clinical study of LDE as a drug vehicle for the treatment of the disease Hungria, V. T., M. C. Latrilha, et al. (2004), Cancer Chemother Pharmacol 53(1): 51-60. Abstract: PURPOSE: Previously we have shown that cholesterol-rich microemulsions that bind to LDL receptors have the ability to concentrate in acute myeloid leukemia cells and in ovarian and breast carcinomas. Thus, LDE may be used as a vehicle for drugs directed against neoplastic cells. Indeed, we subsequently showed that when carmustine is associated with LDE the toxicity of the drug is significantly reduced in patients with advanced cancers. The aim of the present study was to verify whether LDE may be taken up by multiple myeloma cells and whether patients with multiple myeloma respond to treatment with LDE associated with carmustine. METHODS: A total of 131 consecutive volunteer patients with recently diagnosed multiple myeloma classified as clinical stage IIIA had their plasma lipid profile determined. LDE plasma kinetics were performed in 14 of them. Cell uptake of LDE and the cytotoxicity of carmustine associated with the emulsion were evaluated in a multiple myeloma cell line. A pharmacokinetic study of LDE-carmustine was performed in three patients. Finally, an exploratory clinical study of LDE-carmustine (carmustine dose 180 mg/m(2) body surface every 4 weeks) was performed in seven untreated multiple myeloma patients. RESULTS: LDL cholesterol was lower in the 131 multiple myeloma patients than in healthy controls and the fractional clearance rate (FCR, in units per minute) in the 14 multiple myeloma patients was twice that in 14 paired healthy control subjects. Moreover, entry of LDE into multiple myeloma cells was shown to be mediated by LDL receptors. Taken together, these findings indicate that LDE may target multiple myeloma. The exploratory clinical study showed that gammaglobulin decreased by 10-70% (mean 36%) after three cycles and by 25-75% (mean 44%) after six cycles. Furthermore, there was amelioration of symptoms in all patients. Cholesterol concentrations increased after treatment, suggesting that the treatment resulted in at least partial destruction of neoplastic cells with receptor upregulation. Side effects of the treatment were negligible. CONCLUSIONS: Because it targets multiple myeloma and, when associated with an antineoplastic agent, produces therapeutic responses in patients with fewer side effects, LDE has the potential for use as a drug vehicle in the treatment of the disease. |
| Metabolism of cholesterol and apolipoprotein B in celiac disease Vuoristo, M., Y. A. Kesaniemi, et al. (1993), Metabolism 42(11): 1386-91. Abstract: To test the association of cholesterol malabsorption with cholesterol and lipoprotein metabolism, we determined low-density lipoprotein (LDL) apolipoprotein (apo) B kinetics simultaneously with measurements of cholesterol absorption and synthesis in six patients with celiac disease (CD) before and during the gluten-free diet (GFD). The basal condition was characterized by low cholesterol absorption, enhanced cholesterol synthesis, and high removal and transport rate of LDL apo B. The GFD markedly improved cholesterol absorption and decreased intestinal influx of cholesterol, fecal neutral steroids, and cholesterol synthesis. Of plasma total and lipoprotein cholesterol levels, only plasma high-density lipoprotein (HDL) was enhanced by the GFD proportionately to cholesterol absorption. The plasma LDL apo B level remained unchanged because of simultaneous decreases in the fractional catabolic rate (FCR) and transport rate of LDL apo B. In fact, the more cholesterol absorption was improved by the GFD, the more the FCR and transport rate for LDL apo B were decreased, and their reductions were closely related to the decrease in cholesterol synthesis. The present results show that cholesterol absorption, cholesterol synthesis, hepatic B/E receptor activity, and LDL apo B transport rate are closely associated with each other and that their levels can change markedly with no detectable change in serum levels of LDL cholesterol or apo B. |
| Metabolism of cholesterol and low- and high-density lipoproteins in primary biliary cirrhosis: cholesterol absorption and synthesis related to lipoprotein levels and their kinetics Gylling, H., M. Farkkila, et al. (1995), Hepatology 21(1): 89-95. Abstract: Cholesterol absorption, elimination, and synthesis, and low-density lipoprotein (LDL) and high density lipoprotein (HDL) kinetics were studied in patients with mild to severe primary biliary cirrhosis (PBC) (n = 16) to show how this cholestatic disease modified cholesterol and lipoprotein metabolism as compared with healthy controls (n = 50). Serum total and lipoprotein cholesterol and triglyceride levels were similar in the two groups, but in PBC, especially in severe forms, very low density lipoprotein (VLDL) was rich in apoprotein (apo) B and cholesterol and low in triglycerides, whereas LDL was rich in triglycerides and low in esterified cholesterol, and HDL was enriched by surface lipids, phospholipids, and free cholesterol. In severe PBC, the fractional catabolic rate (FCR) for LDL apo B was reduced. The transport rate (TR) for LDL apo B was unaffected and it tended to correlate with the LDL apo B and LDL cholesterol levels in PBC, whereas in the controls the LDL apo B concentration was regulated by both the FCR and TR, and LDL cholesterol was regulated only by FCR. FCR for apo A-I in HDL was unaltered in PBC, but TR for apo A-I was reduced in the severe cases. Cholesterol absorption efficiency was significantly reduced in PBC (14.5 +/- 3.0% in severe PBC and 34.0 +/- 2.5% in mild PBC vs. 47.4 +/- 1.4% in the controls, respectively).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Metabolism of cholesterol and phospholipids in cultured human vascular smooth muscle cells: differences between artery and vein-derived cells and the effect of oxygen partial pressure Savion, N., M. Greemland, et al. (1991), Eur J Cell Biol 55(2): 305-11. Abstract: Human smooth muscle (SM) cells derived from vena saphena magna, aorta abdominalis and arteria mamaria were grown in culture under 40 or 145 mmHg oxygen partial pressure (pO2) and their lipid metabolism studied. Esterification of the cellular 3Hcholesterol was higher by 2.5-fold in artery derived than in vein-derived cells and was slightly higher in cultures exposed to 145 mmHg than to 40 mmHg pO2. Cholesterol efflux in the presence of high density lipoprotein (HDL) in the incubation medium was higher in artery-derived than vein-derived cells. Apolipoprotein (apo) AI also supported cholesterol efflux to a higher extent in artery than in vein-derived cells. Cholesterol efflux in the presence of apo AI was accompanied by a decrease of 50% in cellular 3Hcholesteryl ester in both cell types. SM cultures exposed to 3Hcholine incorporated about 90% of the radioactivity to phosphatidylcholine (PC) and 10% to sphingomyelin (SPM). During 5 days exposure to 3Hcholine, 10 to 15% and 20 to 30% of the newly synthesized PC and SPM, respectively, were released by vein-derived cells into the incubation medium. The relative amount of SPM of the total radioactive phospholipids released by vein-derived cultures was significantly higher in cultures growing under 40 mmHg than 145 mmHg pO2 reaching a value of up to 33% of the radioactive phospholipids in the incubation medium. HDL was shown to serve as an acceptor for phospholipids released by both vein and artery-derived SM cells, while free apo AI supported phospholipid efflux in artery but not in vein-derived SM cells.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Metabolism of cholesterol ester of apolipoprotein B100-containing lipoproteins in dogs: evidence for disregarding cholesterol ester transfer Bailhache, E., F. Briand, et al. (2004), Eur J Clin Invest 34(8): 527-34. Abstract: BACKGROUND: It has been shown that dogs exhibit no cholesterol ester transfer protein (CETP) activity in vitro, in contrast to humans. The aim of our study was to determine modalities of in vivo plasma cholesterol ester turnover in this species, using a kinetic approach with stable isotopes. MATERIALS AND METHODS: Kinetics of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) were studied in seven adult male Beagle dogs using a dual isotope approach through endogenous labelling of both their cholesterol moiety and their protein moiety. A primed constant infusion of both 1,2(13)Cacetate and 5,5,5-2H3leucine enabled us to obtain measurable deuterium enrichments by gas chromatography-mass spectrometry for plasma leucine and apoB100, as well as measurable 13C enrichment by gas chromatography-combustion-isotopic ratio mass spectrometry for unesterified cholesterol and cholesterol ester in the VLDL and LDL. Two identical multicompartmental models (SAAM II) were used together for the analysis of tracer kinetics' data of proteins and cholesterol. RESULTS: Characterization of the apoB100-containing lipoprotein cholesterol ester model allowed determination of kinetic parameters of VLDL and LDL cholesterol ester metabolism. We succeeded in modelling VLDL and LDL cholesterol ester metabolism and apoB100 metabolism simultaneously. Fractional catabolic rate (FCR) of apoB100 and CE had the same values. Introducing cholesterol ester transfer between lipoproteins in the model did not significantly improve the fit. Total VLDL FCR was 2.97 +/- 01.47 h(-1). Approximately one-quarter corresponded to the direct removal of VLDL (0.81 +/- 00.34 h(-1)) and the remaining three-quarters corresponded to the fraction of VLDL converted to LDL, which represented a conversion of VLDL into LDL of 2.16 +/- 01.16 h(-1). Low-density lipoproteins were produced exclusively from VLDL conversion and were then removed (0.031 +/- 0.004 h(-1)) from plasma. CONCLUSION: These kinetic data showed that VLDL cholesterol ester and LDL cholesterol ester metabolism followed VLDL and LDL apoB100 metabolism, and that consequently there is no in vivo transfer of cholesterol ester in dogs. |
| Metabolism of cholesterol esters in cultured macrophages under the action of the calcium antagonists verapamil and nifedipine Dushkin, M. I. and M. V. Ivanova (1991), Biokhimiia 56(5): 812-9. Abstract: Using mouse macrophage cultures, the effects of verapamil and nifedipine on cholesterol ester metabolism were studied with special reference to the following parameters: i) incorporation of 14C-oleate into cholesterol esters (ChE), ii) contents of common and free cholesterol (FCh), iii) removal of 14C-oleate from ChE and incorporation of 3H-FCh into ChE and, iiii) excretion of 3H-Ch from the cells. Verapamil and nifedipine (10-100 microM) decreased the incorporation of 14C-oleate into ChE, increased the concentration of FCh but had no appreciable effect on the concentration of common Ch in macrophages cultured in the presence of acetylated low density lipoproteins. The drugs stimulated the removal of 14C-oleate from cellular ChE. The pharmacological concentrations (25-75 microM) of verapamil and nifedipine increased the excretion of 3H-Ch from ChE of macrophages in the presence of serum and high density lipoproteins. The results obtained suggest that verapamil and nifedipine mediate the antiatherosclerotic effect via reduction of intracellular synthesis of ChE, stimulation of ChE hydrolysis and cholesterol excretion from the cells. |
| Metabolism of cholesterol is altered in the liver of C3H mice fed fats enriched with different C-18 fatty acids Cheema, S. K. and L. B. Agellon (1999), J Nutr 129(9): 1718-24. Abstract: We examined whether the degree of saturation of C-18 fatty acids influenced hepatic cholesterol metabolism in C3H mice. The mice were fed diets containing 20 g/100 g fat, enriched in stearic (18:0), oleic (18:1) or linoleic acid (18:2) with or without 1 g/100 g cholesterol. Plasma total cholesterol concentration was lower in mice fed the 18:0 diet relative to those fed the 18:1- or 18:2-enriched diets (P < 0.05) regardless of dietary cholesterol supplementation. Dietary cholesterol significantly raised hepatic total cholesterol concentration (P < 0.05) in those fed the 18:1- and 18:2-enriched diets, but not in mice fed the 18:0-enriched diet. Dietary cholesterol raised biliary cholesterol concentration (P < 0. 05) in mice fed the 18:1- and 18:2-enriched diets, but not in mice fed the 18:0-enriched diet. The cholesterol saturation index was variably affected by the fat diets. Feeding diets containing cholesterol suppressed the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity and induced acyl coenzyme A:cholesterol acyl transferase (ACAT) activity compared with feeding diets without cholesterol (P < 0.05), indicating that the liver was exposed to dietary cholesterol. Hepatic ACAT activity was lower in mice fed the 18:0-enriched diet compared with those fed the 18:1- or 18:2-enriched diets (P < 0.05). Addition of cholesterol to the 18:1 diet induced the largest increase of hepatic ACAT activity, and this was associated with the enrichment of VLDL with cholesterol. Varying the degree of saturation of C-18 fatty acids influences the metabolism and disposition of hepatic cholesterol. |
| Metabolism of cholesterol, phosphatidylethanolamine and stearylamine analogues of GM1 ganglioside by rat glioma C6 cells Pacuszka, T. and P. H. Fishman (1991), Biochim Biophys Acta 1083(2): 153-60. Abstract: Tritium-labeled neoglycolipids consisting of the oligosaccharide of ganglioside GM1 attached to cholesterol (GM1OSNH-X-CHOL), phosphatidylethanolamine (GM1OS-PE) and stearylamine (GM1OSNHC18) were synthesized and their uptake and metabolism by GM1-deficient rat glioma C6 cells were determined. When the neoglycolipids were added to serum-free culture medium, all three were rapidly taken up by the cells and initially inserted into the plasma membrane based on their resistance to trypsin and their ability to bind cholera toxin. With time, the neoglycolipids underwent internalization as the ratio of cell-associated radioactivity to cell surface toxin binding increased; this process was slow for GM1OSNH-X-CHOL and GM1OS-PE and rapid for GM1OSNHC18. Analysis of lipids extracted from the cells indicated that the neoglycolipids also underwent metabolism to GD1aOS-based analogues. In addition, GM1OSNH-X-CHOL and GM1OSNHC18 were degraded to their GM2OS-based analogues, whereas GM2OS-PE was not detected. In contrast, large amounts of 3H were recovered in the medium from cells treated with GM1OS-PE and the label was associated with material that behaved neither as an oligosaccharide or a neoglycolipid. In the presence of monensin or chloroquine, metabolism of the three neoglycolipids was inhibited. Thus, GM1OS-based neoglycolipids were taken up by the cells, internalized and sorted both to the Golgi apparatus (sialylated to GD1aOS-based analogues) and to lysosomes (hydrolyzed to GM2OS-based analogues). The rate and extent of these processes, however, were strongly influenced by the nature of lipid moiety. |
| Metabolism of chylomicron cholesterol is delayed by estrogen. An in vivo study in the rat Bravo, E., A. Cantafora, et al. (2001), Exp Biol Med (Maywood) 226(2): 112-8. Abstract: In order to test the effects of estrogen on the clearance of cholesterol of dietary origin from the blood and its elimination from the body via the bile in an in vivo animal model, the fate of radioactivity from intravenously injected 3Hcholesterol-labeled chylomicrons was investigated in the rat. The labeled lipoproteins were administered intrajugularly to male rats previously given 17alpha ethinyl estradiol or the vehicle only, and the removal of the radioactivity from the blood and its uptake by the liver and secretion into bile was determined. Experiments were carried out in animals with or without prior drainage (20 hr) of the pool of bile acids in the enterohepatic circulation, to take account of the different demands of the liver for cholesterol in the two conditions. In rats without biliary drainage, estrogen treatment decreased the rate of removal of radioactivity from the blood by about 30% and the recovery of cholesterol in the liver by about 50% in the first 30 min after injection of the labeled chylomicrons. After biliary drainage, however, the recovery of label in the liver after 90 min was similar in estrogen-treated and control animals, although its secretion into bile was markedly reduced in the estrogen-treated group (total biliary secretion in 90 min was 26% of the value found in control rats). In addition, the apolipoprotein E (aopE) content of the serum total lipoproteins was markedly reduced by estrogen. These results provide direct evidence indicating that estrogen retards the elimination of dietary cholesterol from the body via the bile in the rat, and this is likely to be mainly due to a reduced level of apoE in chylomicrons. In view of this, we suggest that the hypothesis that estrogen increases the hepatic uptake of chylomicron cholesterol, and its excretion in the bile during contraceptive and hormone replacement therapy should be re-examined. |
| Metabolism of exogenous cholesterol by rat adrenal mitochondria is stimulated equally by physiological levels of free Ca2+ and by GTP Kowluru, R., T. Yamazaki, et al. (1995), Mol Cell Endocrinol 107(2): 181-8. Abstract: Adrenal mitochondria metabolize cholesterol at inner membrane (IM) cytochrome P450scc. Exogenous and outer membrane (OM) cholesterol are metabolized more slowly due to a limiting transfer of cholesterol from OM to IM. This process is stimulated by in vivo ACTH treatment and inhibited by cycloheximide (CX)-induced depletion of labile regulatory proteins. In isolated rat adrenal mitochondria, GTP enhances the metabolism of exogenous cholesterol, consistent with enhanced intermembrane cholesterol transfer (Xu et al. (1989) J. Biol Chem. 264, 17674), but metabolism of 20 alpha-hydroxycholesterol, which readily traverses mitochondrial membranes, is not affected. The non-hydrolyzable analog, GTP gamma S, completely inhibits the activation of cholesterol metabolism by GTP, suggesting a requirement for GTP hydrolysis. Low concentrations of Ca2+ (0.4-4 microM) stimulate two independent cholesterol transport processes. For exogenous cholesterol, a Ca(2+)-mediated process can replace GTP since each produces comparable stimulation and the combination produces little additional activity. This Ca2+ stimulation is insensitive to GTP gamma S and also to Ruthenium Red (RR), which prevents Ca2+ entry into the matrix. Ca2+ also enhances availability to P450 scc of endogenous OM cholesterol, which accumulates during in vivo CX-inhibition. This stimulation is, however, distinguished by insensitivity to GTP and complete inhibition by RR. Ca2+, therefore, enhances intermembrane transfer of exogenous cholesterol from OM without entry into the matrix through a process which is independently stimulated by GTP. Ca2+ induces transfer of endogenous OM cholesterol through a completely different mechanism involving RR-inhibited matrix changes.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Metabolism of lipoprotein remnants in humans. Studies during intestinal infusion of fat and cholesterol in subjects with varying expression of the low density lipoprotein receptor Eriksson, M., B. Angelin, et al. (1991), Arterioscler Thromb 11(4): 827-37. Abstract: To study the possible importance of the low density lipoprotein (LDL) receptor in regulating the degree of postprandial lipemia, a cholesterol-rich fat emulsion was infused into the duodenum of subjects who were divided into four groups based on the expected variation in the expression of the LDL receptor: young men (n = 11), elderly men (n = 7), male patients on estrogen therapy (n = 5), and patients with familial hypercholesterolemia (n = 9). In familial hypercholesterolemia, fasting plasma levels of lipoproteins of d less than 1.006 g/ml, intermediate density lipoproteins, and LDLs were increased. During the fat infusion, the cholesterol and triglyceride contents in the d less than 1.006 g/ml fraction increased to a similar extent in all groups, whereas a concomitant reduction of LDL cholesterol levels was observed. The degree of the decrease in LDL cholesterol was positively correlated with the observed increase in triglycerides in the d less than 1.006 g/ml fraction. There were no signs of accumulation of intermediate density lipoproteins during infusion in any of the groups studied. The results indicate that the capacity for clearance of chylomicrons and chylomicron remnants is not affected by variation in LDL receptor expression. |
| Metabolism of low-density lipoprotein free cholesterol by human plasma lecithin-cholesterol acyltransferase Fielding, P. E., T. Miida, et al. (1991), Biochemistry 30(35): 8551-7. Abstract: The metabolism of cholesterol derived from 3Hcholesterol-labeled low-density lipoprotein (LDL) was determined in human blood plasma. LDL-derived free cholesterol first appeared in large alpha-migrating HDL (HDL2) and was then transferred to small alpha-HDL (HDL3) for esterification. The major part of such esters was retained within HDL of increasing size in the course of lecithin-cholesterol acyltransferase (LCAT) activity; the balance was recovered in LDL. Transfer of preformed cholesteryl esters within HDL contributed little to the labeled cholesteryl ester accumulating in HDL2. When cholesterol for esterification was derived instead from cell membranes, a significantly smaller proportion of this cholesteryl ester was subsequently recovered in LDL. These data suggest compartmentation of cholesteryl esters within plasma that have been formed from cell membrane or LDL free cholesterol, and the role for HDL2 as a relatively unreactive sink for LCAT-derived cholesteryl esters. |
| Metabolism of oxidized phosphatidylcholines formed in oxidized low density lipoprotein by lecithin-cholesterol acyltransferase Itabe, H., R. Hosoya, et al. (1999), J Biochem (Tokyo) 126(1): 153-61. Abstract: The possible involvement of lecithin-cholesterol acyltransferase (LCAT) in the metabolism of oxidized phosphatidylcholine (PC) in plasma was investigated. A variety of oxidized products are formed from PC following oxidation of low density lipoproteins (LDL). A significant increase in LDL oxidation levels in patients with familial LCAT deficiency (FLD) has been previously demonstrated by a sensitive sandwich ELISA for oxidized LDL using the monoclonal antibody DLH3 which recognizes oxidized products of PC. In the present study, we found that LCAT produces various metabolites from oxidized PC and that oxidized PC molecules in LDL particles serve as substrates. When the neutral lipid fraction was separated by TLC after the incubation of oxidized 1-palmitoyl-2-1-14Clinoleoyl PC with human plasma, a number of radioactive bands were formed in addition to cholesteryl ester. These products were not formed from native 1-palmitoyl-2-1-14Clinoleoyl PC. Plasma from FLD patients also failed to form the additional products from oxidized PC. The addition of dithio-bis(nitrobenzoate) (DTNB), an LCAT inhibitor, or the inactivation of LCAT activity by treating the plasma at 56 degrees C for 30 min abolished the generation of these products from oxidized PC. The activity was recovered in the high density lipoprotein (HDL) fraction but not in the LDL fraction separated from normal plasma. When 1-palmitoyl-2-1-14C(9-oxononanoyl) PC and 1-stearoyl-2-1-14C(5-oxovaleroyl)PC, PC oxidation products that contain short chain aldehydes, were incubated with human plasma, radioactive products in the neutral lipid fraction were observed on TLC. LDL containing oxidized PC was measured by sandwich ELISA using an anti-apolipoprotein B antibody and DLH3. The reconstituted oxidized PC-LDL particles were found to have lost their ability to bind DLH3 upon incubation with HDL, while the reactivity of the reconstituted oxidized PC-LDL remained unchanged in the presence of DTNB. These results suggest that LCAT is capable of metabolizing a variety of oxidized products of PC and preventing the accumulation of oxidized PC in circulating LDL particles. |
| Metabolism of plasma cholesterol and lipoproteins after total resection of the small intestine in patients with parenteral nutrition. Effects of the amount of phospholipids infused Beau, P., J. Ferezou, et al. (1992), Gastroenterol Clin Biol 16(10): 769-76. Abstract: The aim of this study was to investigate the plasma lipoprotein profile in 2 patients treated by parenteral nutrition for total small bowel resection over a 15 month period. According to the amount of infused phospholipids (6 g/d vs 3 g/d), infused during 4 non consecutive 6 month or 6 week periods, HDL-cholesterol, apolipoproteins AI and B plasma levels were 30 to 50% below normal values. During the higher phospholipid supply, cholesterolemia seemed normal; each phospholipid supply decrease was followed by a reduction of cholesterol, phospholipids and apolipoprotein B plasma levels of 40, 50 and 25%, respectively, while HDL-cholesterol and apolipoprotein AI plasma levels remained unchanged. Density gradient ultracentrifugation showed that plasma cholesterol changes were mainly due to cholesterol changes (as free cholesterol associated with phospholipids) located in the density range of 1.019-1.040, reflecting the presence of lipoprotein X-like particles, whose levels remained unchanged during each period. An apolipoprotein E, CII and CIII enrichment of plasma was observed and was more pronounced when patients received higher phospholipid infusion. These results show that, in patients without a small bowel, minor changes in phospholipids supply are responsible for serious alterations of the lipoprotein profile; formation of lipoprotein X-like particles could be favored by the low HDL levels in these patients. |