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PubMed2006

Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models.

It is generally accepted that the lipid formulations of amphotericin B (AMB) are not as potent as conventional AMB on a milligram-per-kilogram basis. We used a neutropenic murine disseminated candidiasis model to compare the in vivo potencies of AMB, liposomal AMB (L-AMB), and AMB lipid complex (ABLC) pharmacodynamically. The pharmacokinetics of the antifungals were examined in serum and in three organs commonly seeded in disseminated candidiasis (kidneys, liver, and lung). Both single-dose time-kill studies and multiple-dosing-regimen studies were used with each of the compounds. Determinations of the numbers of CFU in the kidneys were performed following the administration of three escalating single doses of the polyenes at various times over 48 h. The areas under the time-kill curves (AUTKs) for each dose level of the drugs were compared by analysis of variance (ANOVA). In the multiple-dosing-regimen studies with five Candida isolates, AMB, L-AMB, and ABLC were administered daily for 72 h. The organism burdens in the mouse kidneys were similarly used as the treatment end point. Additional multiple regimen-dosing-studies were performed with a single Candida albicans isolate, and the microbiologic outcomes in four internal organs (kidneys, liver, spleen, and lung) were examined at the end of therapy (48 h). The relationship between the dose and the drug exposure expressed by the pharmacokinetics of the dosing regimens in serum and organ tissue were analyzed by using a maximum-effect model. ANOVA was used to compare the drug exposures necessary to achieve the 25% effective dose (ED25), ED50, ED75, and 1 log10 killing. Comparison of AUTKs suggested that AMB was 4.3- to 5.9-fold more potent than either ABLC or L-AMB. The time-kill curves for both lipid formulations were very similar. In the multiple-dosing-regimen studies, AMB was 5.0- to 8.0-fold more potent than each of the lipid formulations against five Candida isolates in the kidneys. Similar differences in potency (5.1- to 7.2-fold) were observed in the other end organs. The difference in pharmacokinetics in serum accounted for much of the difference in potency between AMB and ABLC (ratio of serum ABLC area under the curve of effective doses to serum AMB area under the curve of effective doses, 1.2). The differences in the kinetics in the various end organs between AMB and L-AMB were better at explaining the disparate potencies at these infection sites (ratio of organ L-AMB area under the curve of effective doses to organ AMB area under the curve of effective doses, 1.1).

Amphotericin B↗
PubMed1986

Early-phase endotoxin tolerance: induction by a detoxified lipid A derivative, monophosphoryl lipid A.

After a sublethal exposure to lipopolysaccharide (LPS) or to lipid A, which is that portion of the LPS molecule associated with endotoxicity, a transient period ensues during which a normally responsive individual is rendered hyporesponsive to LPS-induced toxicity. This period has been defined as early-phase endotoxin tolerance. Recently, a nontoxic derivative of lipid A from Salmonella typhimurium, monophosphoryl lipid A (MPL), was isolated and purified. In this study, we assessed the ability of MPL to induce early endotoxin tolerance. Initial injection of MPL resulted in a dose-dependent stimulation of both serum colony-stimulating factor and serum interferon, indicators of in vivo LPS responsiveness. In contrast, MPL failed to induce the symptoms of endotoxicity which are normally seen after injection of even sublethal amounts of intact endotoxin or lipid A preparations. Injection of MPL on day 0 reduced significantly the amount of LPS-induced serum colony-stimulating factor and interferon produced upon challenge with Escherichia coli LPS 3 days later and also mitigated toxic manifestations, as evidenced by a marked increase in the 50% lethal dose. Like the early tolerance induced by wild-type (toxic) LPS, MPL-induced tolerance was characterized by an accompanying elevation in the number of bone marrow-derived macrophage progenitor cells and by an alteration in bone marrow cell sizing profiles. These results indicate that MPL is effective in inducing a state of LPS-hyporesponsiveness without the toxic side effects of endotoxin and that the structural component(s) necessary for induction of early-phase endotoxin tolerance is contained within MPL.

Animals↗
PubMed1981

Control of membrane lipids in Mycoplasma gallisepticum: effect on lipid order.

Adaptation of Mycoplasma gallisepticum, a sterol-requiring Mycoplasma sp., to growth in a serum-free medium supplemented with cholesterol in decreasing concentrations and with various saturated or unsaturated fatty acids enabled us to control both the cholesterol levels and the membrane fatty acid composition. An estimate of the membrane physical state from fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene indicated that the membrane lipids of native M. gallisepticum were highly ordered. Elongation of the saturated fatty acid chains from 14 to 18 carbon atoms caused only a small increase in the membrane lipid ordering, whereas the introduction of a cis double bond reduced it significantly. Lipid-phase transitions were observed in low-cholesterol-adapted organisms, whose membrane lipids were still highly ordered at the growth temperature.

Cholesterol↗
PubMed1996

Lipid membrane fusion induced by the human immunodeficiency virus type 1 gp41 N-terminal extremity is determined by its orientation in the lipid bilayer.

The amino-terminal extremity of the human immunodeficiency virus type 1 transmembrane protein (gp41) is thought to play a pivotal role in the fusion of virus membranes with the plasma membrane of the target cell and in syncytium formation. Peptides with sequences taken from the human immunodeficiency virus type 1 gp41 fusogenic (synthetic peptides SPwt and SP-2) and nonfusogenic (SP-3 and SP-4) glycoproteins adopt mainly a beta-sheet conformation in the absence of lipid, as determined by attenuated total reflection Fourier transform infrared spectroscopy, and after interaction with large unilamellar liposomes, the beta-sheet is partly converted into an alpha-helical conformation. Peptides SPwt and SP-2 but not SP-3 or SP-4 were able to promote lipid mixing as assessed by fluorescence energy transfer assay and dye leakage in a vesicle leakage assay. By using polarized attenuated total reflection Fourier transform infrared spectroscopy, SPwt and SP-2 were found to adopt an oblique orientation in the lipid membrane whereas SP-3 and SP-4 were oriented nearly parallel to the plane of the membrane. These findings confirm the correlation between the membrane orientation of the alpha-helix and the lipid mixing ability in vitro. Interestingly, the data provide a direct correlation with the fusogenic activity of the parent glycoproteins in vivo.

Amino Acid Sequence↗
PubMed2003

Membrane synthesis, specific lipid requirements, and localized lipid composition changes associated with a positive-strand RNA virus RNA replication protein.

Multifunctional RNA replication protein 1a of brome mosaic virus (BMV), a positive-strand RNA virus, localizes to the cytoplasmic face of endoplasmic reticulum (ER) membranes and induces ER lumenal spherules in which viral RNA synthesis occurs. We previously showed that BMV RNA replication in yeast is severely inhibited prior to negative-strand RNA synthesis by a single-amino-acid substitution in the ole1w allele of yeast Delta9 fatty acid (FA) desaturase, which converts saturated FAs (SFAs) to unsaturated FAs (UFAs). Here we further define the relationships between 1a, membrane lipid composition, and RNA synthesis. We show that 1a expression increases total membrane lipids in wild-type (wt) yeast by 25 to 33%, consistent with recent results indicating that the numerous 1a-induced spherules are enveloped by invaginations of the outer ER membrane. 1a did not alter total membrane lipid composition in wt or ole1w yeast, but the ole1w mutation selectively depleted 18-carbon, monounsaturated (18:1) FA chains and increased 16:0 SFA chains, reducing the UFA-to-SFA ratio from approximately 2.5 to approximately 1.5. Thus, ole1w inhibition of RNA replication was correlated with decreased levels of UFA, membrane fluidity, and plasticity. The ole1w mutation did not alter 1a-induced membrane synthesis, 1a localization to the perinuclear ER, or colocalization of BMV 2a polymerase, nor did it block spherule formation. Moreover, BMV RNA replication templates were still recovered from cell lysates in a 1a-induced, 1a- and membrane-associated, and nuclease-resistant but detergent-susceptible state consistent with spherules. However, unlike nearby ER membranes, the membranes surrounding spherules in ole1w cells were not distinctively stained with osmium tetroxide, which interacts specifically with UFA double bonds. Thus, in ole1w cells, spherule-associated membranes were locally depleted in UFAs. This localized UFA depletion helps to explain why BMV RNA replication is more sensitive than cell growth to reduced UFA levels. The results imply that 1a preferentially interacts with one or more types of membrane lipids.

Bromovirus↗
PubMed1995

Serum lipids four weeks after acute myocardial infarction are a valid basis for lipid lowering intervention in patients receiving thrombolysis.

OBJECTIVE: To compare serum concentrations of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides four weeks after acute myocardial infarction with baseline levels measured within 24 hours after onset of symptoms. DESIGN: A prospective study including 141 patients with acute myocardial infarction who were admitted to the coronary care unit at a general hospital. MEASUREMENTS: Fasting serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. MAIN RESULTS: In patients receiving thrombolytic therapy, no significant differences were found in serum lipids four weeks after admission compared to values estimated within 24 hours from onset of symptoms. In patients not receiving thrombolytic therapy, total cholesterol and low density lipoprotein cholesterol showed a minor increase four weeks after admission compared to values obtained within 24 hours after onset of symptoms. High density lipoprotein cholesterol and triglycerides remained unchanged. CONCLUSIONS: In patients with acute myocardial infarction receiving thrombolytic therapy, serum lipids measured four weeks after onset of infarction are reasonably valid estimates of baseline lipid levels and may be used to decide about lipid lowering interventions. This information can be a basis for actions against hyperlipidaemia early after hospital discharge when the patient is highly motivated to change lifestyles and is still in close contact with a cardiologist or other physician.

Adult↗
PubMed1999

Stress tolerance in a yeast lipid mutant: membrane lipids influence tolerance to heat and ethanol independently of heat shock proteins and trehalose.

The response of a yeast unsaturated fatty acid auxotroph, defective in delta 9-desaturase activity, to heat and ethanol stresses was examined. The most heat- and ethanol-tolerant cells had membranes enriched with oleic acid (C18:1), followed in order by cells enriched with linoleic (C18:2) and linolenic (C18:3) acids. Cells subjected to a heat shock (25-37 degrees C for 30 min) accumulated trehalose and synthesized typical heat shock proteins. Although there were no obvious differences in protein profiles attributable to lipid supplementation of the mutant, relative protein synthesis as determined by densitometric analysis of autoradiograms suggested that hsp expression was different. However, there was no consistent relationship between the synthesis of heat shock proteins and the acquisition of thermotolerance in the lipid supplemented auxotroph or related wild type. Furthermore, trehalose accumulation was also not closely related to stress tolerance. On the other hand, the data presented indicated a more consistent role for membrane lipid composition in stress tolerance than trehalose, heat shock proteins, or ergosterol. We suggest that the sensitivity of C18:3-enriched cells to heat and ethanol may be attributable to membrane damage associated with increases in membrane fluidity and oxygen-derived free radical attack of membrane lipids.

Electrophoresis, Polyacrylamide Gel↗
PubMedDate not supplied

Impaired lipid metabolism in aged mice as revealed by fasting-induced expression of apolipoprotein mRNAs in the liver and changes in serum lipids.

BACKGROUND: Changes in apolipoprotein (Apo) metabolism can cause an increased incidence of diseases such as cardiovascular disorders and diabetes with advancing age. Limited reports are available on this topic, however. OBJECTIVE: To investigate age-related changes in mobilization of stored lipid, we studied the effects of fasting on the gene expression of Apos in the liver as well as serum triglyceride (TG) and cholesterol levels in the serum. METHODS: Using young (6- to 8-month-old) and old (24- to 28-month-old) fasted and re-fed mice, Northern blots of hepatic mRNAs for Apos A-I, A-IV, C-II, C-III, and liver-type fatty acid-binding protein and HPLC analyses of serum lipids were conducted. RESULTS: Fasting induced 4- and 20-fold increases in the mRNA of Apo C-II and A-IV, respectively, in young mice while only 1.1- and 7-fold increases, respectively, were detected in old mice. In contrast, the Apo C-III gene expression was significantly reduced by fasting in the young mice but the reduction was small in the old. In view of the stimulating effect of Apo C-II and A-IV and the inhibiting effect of C-III on lipoprotein lipase (LPL), these findings suggest that the fasting-induced activation of LPL may be considerably decreased in old mice. The amount of TG in very low-density lipoprotein (VLDL), a major form of the transport of TG to peripheral tissues, was significantly greater in the young than in the old mice. Despite possible activation of LPL by fasting, the amount of TG in VLDL, a major form of the transport of TG to peripheral tissues, was significantly greater in the young mice than in the old. It is indicated that the synthesis of VLDL in the liver is high in the young but low in the old mice, which also may be true for the rate of transport of TG. CONCLUSION: The present findings suggest that mobilization of lipids is impaired in old animals due to decreased gene expression of Apos, possibly leading in the long run to excessive lipid accumulation in tissues such as the liver, adipose tissues and blood vessels even in normal feeding, and resulting in an increased incidence of age-related diseases.

Aging↗
PubMed1989

Acute respiratory response of guinea pigs to lipopolysaccharide, lipid A, and monophosphoryl lipid A from Salmonella minnesota.

Exposure to endotoxin has been associated with systemic toxicity, including pulmonary disorders such as byssinosis, as well as with beneficial biologic activities such as adjuvanticity and mitogenicity. The purified lipopolysaccharide (LPS) from endotoxin has been employed to investigate structure-activity relationships for various biologic effects. The current study was undertaken to examine the relationship between LPS structure and its ability to cause respiratory toxicity in guinea pigs after inhalation exposure. Animals were exposed to atmospheres containing 0.076 to 2.1 micrograms/m3 Salmonella minnesota LPS (S. minn. LPS), LPS from the mutant S. minn. Re595, S. minn. Re595 lipid A, and monophosphoryl S. minn. Re595 lipid A (S. minn. Re595 MPL). Each of the LPS aerosols caused increased breathing frequency (f), decreased tidal volume (VT), and airflow disturbance when measured 18 h after the 6-h inhalation exposure. The LPS preparations had equivalent toxicity, whereas the lipid A aerosol had slightly reduced toxicity. The MPL preparation did not produce this respiratory toxicity response. The results indicated that absence of the terminal phosphate group from the reducing end of the lipid A disaccharide destroyed its ability to cause the respiratory effect. These results initiate structure-activity studies of defined LPS in the lung and indicate the possibility of chemically treating endotoxins to remove adverse pulmonary effects.

Animals↗
PubMed1995

In vitro cell injury by oxidized low density lipoprotein involves lipid hydroperoxide-induced formation of alkoxyl, lipid, and peroxyl radicals.

Mounting evidence supports current theories linking lipoprotein oxidation to atherosclerosis. We sought the cellular biochemical mechanism by which oxidized LDL inflicts cell injury. Inhibitors of candidate pathways of cell death were used to treat human fibroblast target cells exposed to oxidized LDL.. Ebselen, which degrades lipid hydroperoxides, inhibited oxidized LDL toxicity, consistent with our recent report that 7 beta-hydroperoxycholesterol (7 beta-OOH chol) is the major cytotoxin of oxidized LDL. Intracellular chelation of metal ions inhibited, while preloading cells with iron enhanced, toxicity, Inhibition of oxidized LDL and 7 beta-OOH chol toxicity by 2-keto-4-thiolmethyl butyric acid, a putative alkoxyl radical scavenger and by vitamin E, probucol and diphenylphenylenediamine, putative scavengers of peroxyl radicals was consistent with the involvement of these radicals in the lethal sequence. Cell death was thus postulated to occur due to lipid peroxidation via a sequence involving lipid hydroperoxide-induced, iron-mediated formation of alkoxyl, lipid, and peroxyl radicals. Pathways involving other reactive oxygen species, new protein synthesis, or altered cholesterol metabolism were considered less likely, since putative inhibitors failed to lessen toxicity. Understanding the mechanism of cell injury by oxidized LDL and its toxic moiety, 7 beta-OOH chol, may indicate specific interventions in the cell injury believed to accompany vascular lesion development.

Alcohols↗
PubMedDate not supplied

Lipid infusion with different triglyceride cores (long-chain vs medium-chain/long-chain triglycerides): effect on plasma lipids and bilirubin binding in premature infants.

The possible beneficial effects of infusing a lipid emulsion containing 50% by weight of medium-chain triglycerides (MCT) compared with a standard long-chain triglyceride (LCT) emulsion were studied in 18 premature neonates (gestational age less than 34 weeks) requiring parenteral nutrition. The infants were assigned in a double-blind manner to receive one of the two lipid emulsions over 17 hours a day as a supplemental regimen for total parenteral nutrition. A lipid load of 1 g/kg per day was initiated on the third day of life and was increased at the rate of 1 g/kg per day until a maximal dose of 3 g/kg per day was obtained on the fifth day of life and maintained thereafter. Both bound and unbound bilirubin decreased with both infusion regimens during the study period. Despite a marked increase in plasma free fatty acid levels (260% in the MCT/LCT group compared with 210% in the LCT group), the fraction of unbound (free) bilirubin was significantly lower in the MCT/LCT group (34% vs 13%). Free fatty acid levels, corrected to albumin, were positively correlated to the percentage of free bilirubin only for the LCT lipid infusion. The finding of a significant elevation of plasma cholesterol levels only in the MCT/LCT group is now under investigation. Use of the MCT-containing emulsion was not associated with a higher frequency of adverse effects than the commonly used LCT-containing emulsion.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilirubin↗
PubMed1987

Elevated lipid peroxidation in rats induced by dietary lipids and N-nitrosodimethylamine and its inhibition by indomethacin monitored via ethane exhalation.

The effect of dietary lipids alone or in combination with an administered carcinogen, N-nitrosodimethylamine (NDMA), on whole body lipid peroxidation was studied in rats in vivo. Groups of rats were fed diets containing 2%, 12.5%, or 25% of either saturated or polyunsaturated fat. Lipid peroxidation in individual animals was determined by measuring the concentration of ethane in exhaled air. Increased ethane exhalation was found in rats when the amount of dietary fat was increased from 2% to 12.5%, but animals receiving 12.5% or 25% fat in the diet exhaled ethane at similar rates. Rats consuming polyunsaturated fat exhaled more ethane than those eating saturated fat. In all groups, NDMA administration drastically increased ethane exhalation. Indomethacin completely blocked the increase in ethane exhalation caused by dietary lipids.

Animals↗
PubMed1982

Successful treatment of familial idiopathic lipid storage myopathy with L-carnitine and modified lipid diet.

We describe the clinical presentation, course, pathologic findings, and biochemical abnormalities found in three adult siblings with an idiopathic lipid storage myopathy. The major presenting symptoms were weakness and cramping, which were profound in one patient, moderate in the second patient, and mild in the third. All three individuals exhibited true myotonic discharges on EMG, normal or mildly depressed muscle free carnitine levels, and borderline delayed ketosis (40 hours) with fasting. Muscle biopsies from all three showed neutral lipid storage. Polymorphonuclear leukocytes and macrophages were vacuolated. No systemic abnormalities of glucose or fat metabolism were identified at rest, with fasting, or with exercise. The two more severely affected patients have responded to medium-chain triglyceride diet and oral carnitine with increased strength and muscle bulk and decreased histochemically observed neutral lipid stores in muscle. One patient has had a resolution of the electrical myotonia. Prednisone therapy in one patient resulted in a loss of cramping sensations but not improvement in strength. We suggest that some cases of idiopathic lipid storage myopathy may be safely and effectively treated with carnitine and medium-chain triglyceride diet.

Carnitine↗
PubMed1975

Cell surface lipids and adhesion. III. The effects on cell adhesion of changes in plasmalemmal lipids.

The two preceding papers of this series suggest that the state of the plasmalemmal lipids affects cell adhesion. Plasmalemmal composition was altered by the experimental incorporation of fatty acids into R1 and R2 positions in the phosphatidyl components of the cell surface. In this paper we report that: (1) If the incorporation is of long chain length fatty acids (saturated) cell adhesion rises. (2) If the incorporation is of unsaturated fatty acids cell adhesion falls as the unsaturation increases. (3) Incorporation has to be extensive to produce a large change in adhesion. (4) Changes in adhesion parallel the plasmalemmal incorporation but do not follow the total cell incorporation. Item (4) argues that it is plasmalemmal and not other membrane lipids that are involved in cell adhesion. Item (3) suggests that bulk membrane properties and not some very specific grouping are involved in the effects of lipids on adhesion. The similar extents of incorporation of the various different fatty acids and the negligible amounts of lysophospholipids in the membranes of cells that have incorporated fatty acids argue that the effects are not due to differential accumulations of these lysolipids when incubations are done with different fatty acids. The changes in adhesion cannot be accounted for by changes in surface charge density since the electrophoretic mobility of the cells is unchanged by these incubations. It is suggested that these effects on adhesion due to changes in plasmalemmal lipids can be explained either in terms of the action of intermembrane van der Waals--London (electrodynamic) forces in cell adhesion or of changes in surface fluidity. These alternatives are discussed.

Adenosine Triphosphate↗
PubMed2006

Domain registration in raft-mimicking lipid mixtures studied using polymer-tethered lipid bilayers.

The degree of domain registration in a liquid-ordered/liquid-disordered phase-separating lipid mixture consisting of 1-stearoyl-2-oleoyl-sn-3-phosphocholine, egg sphingomyelin, and cholesterol (molar mixing ratio of 1:1:1) was studied using three different planar lipid bilayer architectures distinguished by their bilayer-substrate distance d using epifluorescence microscopy. The bilayer systems, which were built layer by layer using Langmuir-Blodgett/Schaefer film depositions, included a solid-supported bilayer (d approximately 15 A) and two polymer-supported bilayers with d approximately 30 A and d approximately 58 A, respectively. Complete domain registration between Langmuir-Blodgett and Schaefer monolayer domains was observed for d approximately 58 A but not in the cases when d approximately 15 A and d approximately 30 A. Building the bilayer layer by layer guaranteed that any preexisting domains were not in registration initially; our data show that the domain registration observed was not caused by lipid flip-flop or by lateral rearrangement of preexisting large-scale domains. Instead, additional studies on bilayer systems with asymmetric lipid composition indicate that preexisting domains in the Langmuir-Blodgett monolayer induce the formation of completely registered domains in the opposite Schaefer monolayer. This study provides insight into possible biophysical mechanisms of transbilayer domain coupling. Our findings support the concept that the formation of transbilayer signaling platforms based on registered raft domains may occur without the active involvement of membrane-spanning proteins.

Cholesterol↗
PubMed2002

Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might be an effective method to improve endothelial function in these patients. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 mg and 80 mg on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease. RESULTS: Patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite substantial lowering of all atherogenic lipid parameters, no improvement of endothelium-dependent vasodilatation was found (P > 0.8). CONCLUSIONS: We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction.

Anticholesteremic Agents↗
PubMed1996

Normolipidemic xanthelasma palpebrarum: lipid composition, cholesterol metabolism in monocyte-derived macrophages, and plasma lipid peroxidation.

The lipid compositions of 8 normolipidemic xanthelasma palpebrarum (XP) lesions were analyzed using thin-layer chromatography, with the adjacent uninvolved skin used as control. The lesions were found to be composed predominantly of cholesterol, mostly cholesteryl ester, whereas in the control specimens phospholipids predominated. The degradation rates of 125I-low-density lipoprotein (LDL), oxidized LDL, and acetyl LDL, and the rates of intracellular cholesterol synthesis from 1,2-(14)C-acetate, in blood monocyte-derived macrophages (MDM) from 3 normolipidemic patients, were similar to those of MDM from 3 normal control subjects. The mean levels of lipid peroxides and conjugated dienes under basal conditions, as well as following the addition of a free radical-generating compound (2,2-azobis-2-amidinopropane hydrochloride) to the plasma of 14 normolipidemic XP patients were significantly higher than those of 14 age- and sex-matched normal controls. We conclude that the predominant lipid accumulated in normolipidemic XP lesions is cholesteryl ester, but there is no evidence for intrinsic cellular cholesterol metabolism derangement in blood MDM from patients which could account for this. Since macrophage cholesterol accumulation can also result from enhanced uptake of increased levels of oxidized LDL, the increased plasma lipid peroxidation (derived from oxidized LDL) might lead to accumulation of cholesterol in macrophages and formation of foam cells via this mechanism.

Adult↗
PubMed1993

Infusion of EPA and DHA lipid emulsions: effects on heart lipids and tolerance to ischaemia-reperfusion in the isolated rat heart.

The aim of the present study was to examine the effect of acute infusion of lipid emulsions enriched with either docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) on heart lipids, tolerance to infusion and to ischaemia-reperfusion. Isolated rat hearts were subjected to a 10 min lipid infusion period prior to 25 min of total global ischaemia and 30 min of reperfusion. Effects on physiology and metabolism were recorded during infusion and reperfusion. A more than doubled increase of DHA and a 12-fold increase of EPA in terms of relative concentration was demonstrated in the free fatty acid fraction after infusion with the respective triglyceride emulsions, without any profound change in physiology. High levels of DHA were associated with a reduced recovery of left ventricular developed pressure (LVDP) and increased release of lactate dehydrogenase (LDH) during reperfusion, while the hearts infused with the EPA-emulsion showed a recovery comparable to the control group. Heart lipid peroxidation, evaluated by release of thiobarbituric acid reactive substances (TBARS) in effluate, was about 4-fold higher in the DHA-group compared to the EPA-group during start of reperfusion and may in part explain the reduced recovery observed in these hearts. The present study demonstrates enrichment of DHA and EPA in the free fatty acid fraction after a short period of infusion. Protective effects of the emulsions were not found, instead the data indicate harmful effects of DHA during ischaemia-reperfusion. However, the presence of TBARS in this emulsion could have influenced the results.

Animals↗