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PubMedDate not supplied

[Intensity of lipid peroxidation and its relation to changes in the composition and antioxidative properties of lipids in acute viral hepatitis].

Interrelationship between the patterns of lipid peroxidation (diene conjugates and the lipid antioxidative activity) and alterations in lipid composition (content of total lipids, phospholipids and cholesterol) was studied in blood serum of patients with acute viral hepatitis and in healthy donors. An increase in content of lipids in blood serum of the patients with the hepatitis but not the intensity of peroxidation reactions in lipids was found to be responsible for the increase in content of the lipid peroxidation products in blood serum. With an increase in severity of the disease relative content of phospholipids in the total lipid fraction as well as antioxidative activity of lipids were elevated, while relative content of cholesterol and level of lipid oxidation were lowered.

Acute Disease↗
PubMed1986

Role of lipids in sarcoplasmic reticulum: a higher lipid content is required to sustain phosphoenzyme decomposition than phosphoenzyme formation.

Enzyme preparations with variable phospholipid contents were obtained by removing lipids from sarcoplasmic reticulum with deoxycholate. Preparations containing from 90 to 37 phospholipids per enzyme showed normal values of both Ca2+-ATPase activity and steady-state phosphoenzyme levels. Fractions containing 37 to 23 phospholipids per enzyme had a reduced ATPase activity but normal phosphoenzyme levels, showing that in this range of lipid content the ATPase reaction is inhibited in a reaction step subsequent to phosphoenzyme formation but prior to phosphoenzyme decomposition. Delipidation below 23 lipids per enzyme caused a marked reduction of the amount of phosphoenzyme formed, so that although both reactions require lipids, fewer lipids are required for phosphoenzyme formation than for decomposition. The effect of lipid removal could be completely reversed by readdition of lipids to fractions containing more than 11 lipids per enzyme. It is proposed that phosphoenzyme formation requires full occupancy of a boundary domain of 23 lipids per enzyme, and that the selective inhibition of phosphoenzyme decomposition at higher lipid contents is caused by a decrease in the rotational mobility of the enzyme.

Animals↗
PubMed1984

The influence of lipid composition on the barrier properties of band 3-containing lipid vesicles.

Band 3 protein has been incorporated into lipid vesicles consisting of 94:6 (molar ratio) egg phosphatidylcholine-bovine heart phosphatidylserine or total erythrocyte lipids by means of a Triton X-100 Bio-Beads method, with an additional sonication step prior to the removal of the detergent. This methods results, for both types of band 3 lipid vesicles, in rather homogeneous vesicles with comparable protein content and vesicle trap. Freeze-fracture electron microscopy revealed that band 3-egg phosphatidylcholine-bovine heart phosphatidylserine vesicles have considerably more intramembrane particles as compared to the band 3-erythrocyte lipid vesicles. The dimensions of the nonspecific permeation pathways present in the band 3-lipid vesicles were measured using an influx assay procedure for nonelectrolytes of different size, in which the vesicles were sampled and subsequently freed from nonenclosed labeled permeant by means of gel-filtration. The band 3-egg phosphatidylcholine-bovine heart phosphatidylserine vesicles have nonspecific permeation pathways (pores), with diameters of up to 60 A. In contrast, the band 3-total erythrocyte lipid vesicles are more homogeneous and show much smaller nonspecific permeation pathways, having a diameter of about 12 A. These results suggest that the nonspecific permeability of the band 3-lipid vesicles is strongly lipid-dependent. Increase in specific anion permeability expected as a consequence of the presence of band 3 in the erythrocyte lipid vesicles was found to be very limited. However, stereospecific, phloretin-inhibitable D-glucose permeability could clearly be demonstrated in these vesicles. The difference of the nonspecific permeability of the band 3-egg phosphatidylcholine-bovine heart phosphatidylserine vesicles and band 3-erythrocyte lipid vesicles, is discussed in the light of the presence of defects at the lipid/protein interface and protein aggregation, which may induce formation of pores.

Animals↗
PubMed1987

Development of intracellular lipid deposits in the lipid-laden cells of atherosclerotic lesions. A cytochemical and ultrastructural study.

In atherosclerotic lesions of rabbits fed a cholesterol-rich diet, the lipid deposits of foam cells derived from monocytes, smooth muscle and endothelial cells were studied by physical, cytochemical and ultrastructural methods. Beginning with the third week of diet, the lipid material that could be visualized at the light microscope level by Oil red O and Nile red staining was progressively accumulated in the intimal cells of the atherosclerotic lesions. In the early stages of foam cell formation, the deposits occurred especially as intracytoplasmic non-membrane bound lipid inclusions (lipid droplets). In polarizing microscopy these appeared as a mixture of iso-, and anisotropic material. The latter were birefringent and showed an axial symmetry with a black cross image, suggesting that the lipids were in a liquid crystalline state. In chemically-fixed specimens, the content of lipid inclusions was preserved in various degrees. In freeze-fractured preparations they displayed a layered onion-like arrangement with smooth cleavage faces surrounding an amorphous core. Upon incubation with filipin, that specifically binds to 3 beta-hydroxysterols, the peripheral layers of the inclusions were labeled, revealing the existence of unesterified cholesterol. In the advanced stages of foam cell formation, lipids were additionally accumulated in the lysosomal compartment as polymorphic multilamellar structures concentrically arranged, with cleavage faces devoid of intralamellar particles. The presence of acid phosphatase showed that these features were modified lysosomes and were tentatively named lysosomal lipid bodies. In the latest stages examined cholesterol crystals developed within lysosomal lipid bodies usually enclosed in multilamellar structures. This lipid coat may represent the place of crystal formation and presumably acts as barrier for the turnover of the crystalline cholesterol, thus impeding plaque regression.

Acid Phosphatase↗
PubMed2005

Effects of lipid composition on the membrane activity and lipid phase behaviour of Vibrio sp. DSM14379 cells grown at various NaCl concentrations.

The membrane lipid composition of living cells generally adjusts to the prevailing environmental and physiological conditions. In this study, membrane activity and lipid composition of the Gram-negative bacterium Vibrio sp. DSM14379, grown aerobically in a peptone-yeast extract medium supplemented with 0.5, 1.76, 3, 5 or 10% (w/v) NaCl, was determined. The ability of the membrane to reduce a spin label was studied by EPR spectroscopy under different salt concentrations in cell suspensions labeled with TEMPON. For lipid composition studies, cells were harvested in a late exponential phase and lipids were extracted with chloroform-methanol-water, 1:2:0.8 (v/v). The lipid polar head group and acyl chain compositions were determined by thin-layer and gas-liquid chromatographies. (31)P-NMR spectroscopy was used to study the phase behaviour of the cell lipid extracts with 20 wt.% water contents in a temperature range from -10 to 50 degrees C. The results indicate that the ability of the membrane to reduce the spin label was highest at optimal salt concentrations. The composition of both polar head groups and acyl chains changed markedly with increasing salinity. The fractions of 16:0, 16:1 and 18:0 acyl chains increased while the fraction of 18:1 acyl chains decreased with increasing salinity. The phosphatidylethanolamine fraction correlated inversely with the lysophosphatidylethanolamine fraction, with phosphatidylethanolamine exhibiting a minimum, and lysophosphatidylethanolamine a maximum, at the optimum growth rate. The fraction of lysophosphatidylethanolamine was surprisingly high in the lipid extracts. This lipid can form normal micellar and hexagonal phases and it was found that all lipid extracts form a mixture of lamellar and normal isotropic liquid crystalline phases. This is an anomalous behaviour since the nonlamellar phases formed by total lipid extracts are generally of the reversed type.

Biophysical Phenomena↗
PubMed1997

Gene transfer mediated by cationic lipids: lack of a correlation between lipid mixing and transfection.

Complexes of DNA with cationic lipids are used to transfect eukaryotic cells. The mechanism of transfection is unknown, but it has been suggested that the complexes are taken up into the cell by endocytosis, after which fusion of the cationic lipids with the membranes of intracellular vesicles would allow the DNA to escape into the cytoplasm. Here, we have compared transfection of CHO-K1 cells with lipid mixing measured by fluorescence assays, using liposomes or complexes with plasmid DNA of the cationic lipids 1,2 dioleolyl-3-N, N, N,-trimethylammonium-propane (DOTAP), N-[2,3-(dioleoyloxy)propyl]-N, N, N,-trimethylammonium (DOTMA), or combinations of these lipids with dioleoylphosphatidylethanolamine (DOPE), at various lipid/DNA charge ratios. Mixing of the lipids of the complexes or liposomes with cellular membranes occurred readily at 37 degrees C, and was more efficient with liposomes than with complexes. Lipid mixing was inhibited at low temperatures (0-17 degrees C), by the presence of NH(4)Cl in the medium, and by low extracellular pH, indicating the involvement of the endocytic pathway in entry. In the absence of DOPE, there was no correlation between the efficiency of lipid mixing and the efficiency of transfection. Moreover, although DOPE, which is thought to promote membrane fusion, enhanced transfection, it did not always enhance lipid mixing. Neither the size nor the zeta potential of the complexes were clearly associated with transfection efficiency. Therefore, although fusion between the lipids of the complexes and cellular membranes takes place, a step at a later stage in the transfection process determines the efficiency of transfection.

Ammonium Chloride↗
PubMed1998

Lipids in total extracts from Acholeplasma laidlawii A pack more closely than the individual lipids. Monolayers studied at the air-water interface.

Pressure-area curves were obtained at 25, 35 and 45 degrees C for total lipid extracts and four individual glucolipids isolated from Acholeplasma laidlawii strain A-EF22. The glucolipids are 1,2-diacyl-3-0-(alpha-D-glucopyranosyl)-sn-glycerol (MGlcDAG), 1,2 -diacyl-3-0-[alpha-D-glucopyranosyl-(1-->2)-0-alpha-D-glucopyranosyl] -sn-glycerol (DGlcDAG), 1,2-diacyl-3-0-[alpha-D-glucopyranosyl-(1-->2)-0-(6-0-acyl-alpha-D-gluco pyranosyl)]-sn-glycerol (MADGlcDAG), and 1,2-diacyl-3-0-[glycerophosphoryl-6-0-(alpha-D-glucopyranosyl-(1-- >)-0-alpha-D-glucopyranosyl)]-sn-glycerol (GPDGlcDAG). The total lipid extracts were obtained from A. laidlawii, grown at 37 degrees C with fatty acids of varying degrees of unsaturation and chain length. The mean surface area per molecule was obtained from these pressure-area curves at surface pressures equal to 10, 20, 30 and 40 mN/m. It was found that the interfacial area of the lipids increases with increasing degree of unsaturation, but is nearly independent of the acyl chain length at constant unsaturation. The surface charge density varied between 4.7 x 10(-3) e-/angstrom(2) and 9.4 x 10(-3) e-/angstrum(2) for the total lipid extracts studied, but did not exhibit any consistent dependence on variations in degree of unsaturation or acyl chain length. The mean area per molecule was found to be smaller for the total lipid extracts than for the individual lipids. It is concluded that the bacterium strives to regulate its lipid composition in such a way that the packing of the lipids in the membrane is appropriately tight, and/or to keep a slight negative spontaneous curvature of the lipid bilayer of the cell membrane ("optimal packing"). This is in accordance with the physico-chemical model for the regulation of the lipid composition in the membrane of A. laidlaiwii previously presented by us (see e.g. Andersson, A.-S., Riffors, L., Bergqvist, M., Persson, S. and Lindblom, G. (1996) Biochemistry 35, 11119-11130).

Acholeplasma laidlawii↗
PubMed2000

Surface charge markedly attenuates the nonlamellar phase-forming propensities of lipid bilayer membranes: calorimetric and (31)P-nuclear magnetic resonance studies of mixtures of cationic, anionic, and zwitterionic lipids.

The lamellar/nonlamellar phase preferences of lipid model membranes composed of mixtures of several cationic lipids with various zwitterionic and anionic phospholipids were examined by a combination of differential scanning calorimetry and (31)P NMR spectroscopy. All of the cationic lipids utilized in this study form only lamellar phases in isolation. Mixtures of these cationic lipids with zwitterionic strongly lamellar phase-preferring lipids such as phosphatidylcholine form only the lamellar liquid-crystalline phase even at high temperatures, as expected. Moreover, mixtures of these cationic lipids with strongly nonlamellar phase-preferring zwitterionic lipids such as phosphatidylethanolamine exhibit a markedly reduced propensity to form inverted nonlamellar phases, again as expected. However, when mixed with anionic lipids such as phosphatidylserine, phosphatidylglycerol, cardiolipin, or phosphatidic acid, a marked enhancement of nonlamellar phase-forming propensity occurs, despite the fact both components of the mixture are nominally lamellar phase-preferring. An examination of the lamellar/nonlamellar phase transition temperatures and the nature of the nonlamellar phases formed, as a function of temperature and of the composition of the mixture, indicates that the propensity to form inverted nonlamellar phases is maximal in mixtures where the mean surface charge of the membrane surface approaches neutrality and decreases markedly with increases in the density of positive or negative charge at the membrane surface. Moreover, the onset temperatures of the reversed hexagonal phase rise more steeply than do those of the inverted cubic phase as the ratio of cationic and anionic lipids is varied, suggesting that the formation of inverted hexagonal phases is more sensitive to this surface charge effect. These results indicate that surface charge per se is a significant and effective modulator of the lamellar/nonlamellar phase preferences of membrane lipids and that charged group interactions at membrane surfaces may have a major role in regulating this particular membrane property.

Anions↗
PubMed1995

Integration of a K+ channel-associated peptide in a lipid bilayer: conformation, lipid-protein interactions, and rotational diffusion.

The 26-residue peptide of sequence KEALYILMVLGFFGFFTLGIMLSYIR, which contains the single putative transmembrane domain of a small protein that is associated with slow voltage-gated K+ channels, has been incorporated in bilayers of dimyristoylphosphatidylcholine by dialysis from 2-chloroethanol to form complexes of homogeneous lipid/peptide ratio. Fourier transform infrared spectroscopy indicates that the peptide is integrated in the lipid bilayer wholly in a beta-sheet conformation. The electron spin resonance spectra of spin-labeled lipids in the lipid/peptide complexes contain a component corresponding to lipids whose chains are motionally restricted in a manner similar to those of lipids at the hydrophobic surface of integral transmembrane proteins. From the dependence of the lipid spin label spectra on the lipid/peptide ratio of the complexes, it is found that ca. 2.5 lipids per peptide monomer, independent of the species of spin-labeled lipid, are motionally restricted by direct interaction with the peptide in the bilayer. This value would be consistent with, e.g., a beta-barrel structure for the peptide in which the beta-strands either are strongly tilted or have a reverse turn at their center. A preferential selectivity of interaction with the peptide is observed for the negatively charged spin-labeled lipids phosphatidic acid, stearic acid, and phosphatidylserine, which indicates close proximity of the positively charged residues at the peptide termini to the lipid headgroups. The saturation-transfer electron spin resonance spectra of the peptide spin-labeled at a cysteine residue replacing Leu18 evidence rather slow rotational diffusion in the lipid complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Poly(ethylene glycol)-lipid conjugates promote bilayer formation in mixtures of non-bilayer-forming lipids.

The influence of poly(ethylene glycol)-lipid conjugates on phospholipid polymorphism has been examined using 31P-NMR and freeze--fracture electron microscopy. An equimolar mixture of dioleoylphosphatidylethanolamine (DOPE) and cholesterol adopts the hexagonal (HII) phase when hydrated under physiological conditions but can be stabilized in a bilayer conformation when a variety of PEG-lipid conjugates are included in the lipid mixture. These PEG conjugates produced an increase in the bilayer to hexagonal (HII) phase transition temperature and a broadening of the temperature range over which both phases coexisted. Further, the fraction of phospholipid adopting the bilayer phase increased with increasing mole fraction of PEG-lipid such that at 20 mole % DOPE--PEG2000 no HII phase phospholipid was observed up to a least 60 degrees C. Increasing the size of the PEG moiety from 2000 to 5000 Da (while maintaining the PEG--lipid molar ratio constant) increased the proportion of lipid in the bilayer phase. In contrast, varying the acyl chains of the PE anchor had no effect on polymorphic behavior. PEG--lipid conjugates in which ceramide provides the hydrophobic anchor also promoted bilayer formation in DOPE:cholesterol mixtures but at somewhat higher molar ratios compared to the corresponding PEG--PE species. The slightly greater effectiveness of the PE conjugates may result from the fact that these derivatives also possess a net negative charge. Phosphorus NMR spectroscopy indicated that a proportion of the phospholipid in DOPE:cholesterol:PEG--PE mixtures experienced isotropic motional averaging with this proportion being sensitive to both temperature and PEG molecular weight. Surprisingly, little if any isotropic signal was observed when PEG--ceramide was used in place of PEG--PE. Consistent with the 31P-NMR spectra, freeze-fracture electron microscopy showed the presence of small vesicles (diameter <200 nm) and lipidic particles in DOPE:cholesterol mixtures containing PEG--PE. We conclude that the effects of PEG--lipid conjugates on DOPE:cholesterol mixtures are 2-fold. First, the complementary "inverted cone" shape of the conjugate helps to accommodate the "cone-shaped" lipids, DOPE and cholesterol, in the bilayer phase. Second, the steric hindrance caused by the PEG group inhibits close apposition of bilayers, which is a prerequisite for the bilayer to HII phase transition.

Cholesterol↗
PubMed1999

Preferential distribution of amphotericin B lipid complex into human HDL3 is a consequence of high density lipoprotein coat lipid content.

The purpose of this study was to determine the plasma lipoprotein (LP) distribution of amphotericin B (AmpB) and amphotericin B lipid complex [ABLC; Abelcet composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG)] and define the relationship between LP lipid concentration and composition and the distribution of AmpB and ABLC in human plasma with varying total and lipoprotein cholesterol and triglycerides. AmpB and ABLC at a concentration of 20 microg amphotericin B/mL were incubated in plasma obtained from different human subjects (n = 7) for 60 min at 37 degrees C. Following these incubations plasma samples were separated into their high-density lipoprotein (HDL), triglyceride-rich lipoprotein (TRL; which contains very low-density lipoproteins and chylomicrons), low-density lipoprotein (LDL), and lipoprotein-deficient (LPDP) fractions by density-gradient ultracentrifugation (UC) and each fraction was assayed for AmpB using high-pressure liquid chromatography (HPLC). The HDL fraction was further separated into its HDL3 and HDL2 subclasses by UC and assayed for AmpB using HPLC. Separation of HDL into its subclasses was confirmed by gel electrophoresis. To assess the influence of modified lipoprotein concentrations and lipid composition on the plasma distribution of AmpB and ABLC, these compounds were incubated in plasmas from human subjects with varying total and lipoprotein lipid concentrations. In addition, to demonstrate that alterations in HDL lipid composition influence the plasma distribution of ABLC, ABLC (20 microg amphotericin B/mL) was incubated in plasma pretreated with dithionitrobenzoate (DTNB, a compound which inhibits lecithin:cholesterol acyltransferase conversion of HDL3 free cholesterol to esterified cholesterol) 18 h prior to the experiment or in untreated plasma for 60 min at 37 degrees C. Total plasma and lipoprotein cholesterol (TC), free cholesterol (fC), esterified cholesterol (CE), triglyceride (TG), phospholipid (PL), and protein (TP) concentrations in each human sample were determined by enzymatic assays. When AmpB was incubated in human plasmas of varying lipid concentrations, the majority of the drug was recovered in the LPDP fraction. However, the majority of AmpB was recovered in the HDL3 fraction following the incubation of ABLC. Differences in lipid coat content (fC and PL) carried by HDL influenced the distribution of ABLC within plasma of different human subjects. These findings were confirmed by the DTNB treatment experiments. These findings suggest that the association of AmpB with DMPC and DMPG to form drug-lipid complexes modifies the plasma distribution of the AmpB. In addition, the distribution of ABLC among plasma lipoproteins of different human subjects is defined by the HDL lipid coat content and is possibly an important consideration when evaluating the pharmacokinetics, toxicity, and activity of these compounds following administration to humans with differing plasma lipid concentrations.

Amphotericin B↗
PubMedDate not supplied

Lipid matters: nicotinic acetylcholine receptor-lipid interactions (Review).

Ligand-gated ion channels mediate fast intercellular communication in response to endogenous neurotransmitters. The nicotinic acetylcholine receptor (AChR) is the archetype molecule in the superfamily of these membrane proteins. Early electron spin resonance studies led to the discovery of a lipid fraction in direct contact with the AChR, with rotational dynamics 50-fold slower than those of the bulk lipids. This AChR-vicinal lipid region has since been postulated to be a possible site of lipid modulation of receptor function. The polarity and molecular dynamics of solvent dipoles-mainly water-of AChR-vicinal lipids in the membrane have been studied with Laurdan extrinsic fluorescence, and Forster-type resonance energy transfer (FRET) was introduced to characterize the receptor-associated lipid microenvironment. FRET enabled one to discriminate between the bulk lipid and the AChR-vicinal lipid. The latter is in a liquid-ordered phase and exhibits a higher degree of order than the bulk bilayer lipid. Changes in FRET efficiency induced by fatty acids, phospholipids and cholesterol also led to the identification of discrete sites for these lipids on the AChR protein. After delineating the topography of the AChR membrane-embedded domains with fluorescence methods, sites for steroids are being explored with site-directed mutagenesis and patch-clamp recording. Pyrene-labelled Cys residues in alphaM1, alphaM4, gammaM1 and gammaM4 transmembrane regions were found to lie in a shallow position. For M4 segments, this is in agreement with a canonical linear alpha-helix; for M1, it is necessary to postulate a substantial amount of non-helical structure, and/or of kinks, to rationalize the shallow location of Cys residues. Mutations of Thr422, a residue close to the extracellular-facing membrane hemilayer in alphaM4, affect the steroid modulation of AChR function, suggesting its involvement in steroid-AChR interactions.

2-Naphthylamine↗
PubMed1978

Essentiality of biotin for channel catfish (Ictalurus punctatus) fed lipid and lipid-free diets.

A 3 X 2 factorial feeding study was conducted with channel catfish (Ictalurus punctatus) to evaluate effects of biotin, no biotin, or a biotin antagonist (avidin) in lipid and lipid-free diets. At 10 weeks, fish fed diets containing lipid were significantly larger than fish fed lipid-free diets. At 20 weeks, fish fed diets containing avidin had grown significantly less than those fed the other diets. At 22 weeks, fish fed the lipid diet supplemented with biotin had grown significantly more than those fed the lipid diet without biotin. Fish fed the lipid diet with avidin were found to be anemic and exhibited a marked depigmentation of the skin. Fish fed biotin in lipid and lipid-free diets had higher liver pyruvate carboxylase activity than fish fed diets without supplemental biotin. These results indicate that channel catfish require an exogenous source of biotin for maximum rates of growth and lipid utilization.

Animals↗
PubMed1982

Lipid-dependent membrane enzymes. A kinetic model for cooperative activation in the absence of cooperativity in lipid binding.

The dependence of integral membrane enzymes on lipid activators in analyzed in terms of multiple binding site kinetics. Rate equations for an enzyme with n independent and indentical lipid binding sites are derived for the case that enzyme activity is proportional to the total amount of lipid bound, or that only fully substituted enzyme is active. A third equation applies to the case that lipids bind with infinite cooperativity to give fully substituted and active enzyme. None of the three models was entirely consistent with existing experimental data. The following kinetic model is shown to accommodate the degree of cooperativity observed in lipid activation experiments as well as the number of independent lipid-binding sites determined by electron-spin resonance measurements. The membrane enzyme is assumed to have n non-interacting and identical lipid-binding sites. Only fully substituted enzyme (ELn) and the next most highly substituted forms such as ELn-1 and ELn-2 may possess enzyme activity. These assumptions lead to cooperativity in activation. Cooperativity reaches a maximum when enzyme activity starts to appear with about 80% of the full lipid substitution. The increase in cooperativity is accompanied by a decrease in the lipid concentration required for half-maximal activation. Further kinetic aspects of a dynamic boundary lipid layer around integral membrane enzymes are discussed.

Allosteric Regulation↗
PubMed1996

Differential induction of IL-1 beta and IL-6 production by the nontoxic lipid A from Porphyromonas gingivalis in comparison with synthetic Escherichia coli lipid A in human peripheral blood mononuclear cells.

Porphyromonas gingivalis 381 lipid A possesses 1-phospho beta(1-6)-linked glucosamine disaccharide with 3-hydroxy-15-methylhexadecanoyl and 3-hexadecanoyloxy-15-methylhexadecanoyl groups at the 2- and 2'-positions, respectively. P. gingivalis lipid A indicated lower activities in inducing interleukin-1 beta (IL-1 beta) mRNA expression, pro-IL-1 beta protein synthesis and IL-1 beta production than those of synthetic Escherichia coli lipid A (compound 506) in human peripheral blood mononuclear cells (PBMC). The induction of IL-6 mRNA and IL-6 synthesis by P. gingivalis lipid A were comparable to those of compound 506. Herbimycin A, H-7 and H-8, inhibitors of tyrosine kinase, protein kinase C and cyclic nucleotide-dependent protein kinase, inhibited P. gingivalis lipid A- and compound 506-induced IL-1 beta and IL-6 synthesis. W-7, an inhibitor of calmodulin (CaM) kinase, inhibited only P. gingivalis lipid A-induced IL-1 beta production. The result suggests that the CaM kinase-dependent cascade is involved in the down-regulation of IL-1 beta production by P. gingivalis lipid A. P. gingivalis lipid A and compound 506 also functioned in the induction of tyrosine and serine/threonine phosphorylation of several proteins in PBMC. P. gingivalis lipid A inhibited specific binding of fluorescein-labelled E. coli LPS to the PBMC. The nontoxic lipid A of P. gingivalis, having a chemical structure different from toxic compound 506, appears to induce the up- and down-regulation of the differential cytokine-producing activities following the activation of various intracellular enzymes including the CaM kinase through the common receptor sites of LPS.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1979

Lipid A and anti-lipid A.

Lipid A in free form, in crude antigen preparations, and on Formalin-treated Escherichia coli and Salmonella minnesota R595 was employed in studies of its antigenic composition, immunogenicity, and availability on gram-negative bacteria. Analyses with immunodiffusion and crossed immunoelectrophoresis of isolated lipid A preparations revealed three components. Inhibition experiments with enzyme-linked immunosorbent assay showed that the lipid A structure was not exposed on the tested smooth or rough E. coli strains or on S. minnesota R595. In crude O antigen preparations from some of the strains, however, lipid A was available for reaction with antibodies. The inaccessibility of lipid A on the bacterial surface may explain the poor protective capacity of anti-lipid A antibodies against bacterial infections. An enzyme-linked immunosorbent assay was more sensitive for measuring anti-lipid A antibody activity than indirect hemolysis or indirect hemagglutination. With an enzyme-linked immunosorbent assay it was shown that in rabbits the immunogenicity of lipid A was approximately the same when coated on erythrocytes or, as is more commonly done, when lipid A-coated hydrolyzed bacteria were used. Some antisera from rabbits immunized with E. coli of different serotypes showed activity against lipid A, with a higher frequency for antisera from rabbits immunized with R mutants.

Antibodies, Bacterial↗
PubMed2000

Lipid concentrations and the use of lipid lowering drugs: evidence from a national cross sectional survey.

OBJECTIVE: To evaluate the prevalence of the use of lipid lowering agents and its relation to blood lipid concentrations in English adults. DESIGN: Cross sectional survey. SETTING: England, 1998. PARTICIPANTS: Nationally representative sample of 13 586 adults (aged >/=16 years) living in non-institutional households. MAIN OUTCOME MEASURES: Mean blood concentrations of total cholesterol and high density lipoprotein (HDL) cholesterol, and the ratio of total cholesterol to HDL cholesterol, in participants classified by age and sex; prevalence of raised total cholesterol concentrations and increased ratio of total to HDL cholesterol; prevalence of use of lipid lowering agents and the lipid concentrations of people taking them. RESULTS: Mean total cholesterol concentrations were 5.47 (SE 0. 02) mmol/l in men and 5.59 (0.02) mmol/l in women. Mean HDL cholesterol concentrations were 1.28 (0.01) mmol/l in men and 1.55 (0.01) mmol/l in women. Overall, of 10 569 adults who had a valid cholesterol measurement taken 7133 (67.5%; 95% confidence interval 66.5% to 68.4%) had a total cholesterol concentration >/=5 mmol/l, 2804 (26.5%; 25.7% to 27.4%) had a ratio of total cholesterol to HDL cholesterol >/=5 mmol/l, and 237 (2.2%; 1.9% to 2.5%) reported taking lipid lowering drugs. Of 117 participants with no history of cardiovascular disease but whose estimated 10 year risk of coronary heart disease was >/=30% and whose total cholesterol concentration was >/=5 mmol/l, four (3%) were taking lipid lowering drugs. Of 385 adults aged 16-75 with a history of coronary heart disease and eligible for lipid lowering treatment, 114 (30%; 25% to 34%) were taking lipid lowering drugs, of whom only 50 (44%; 35% to 53%) had a total cholesterol concentration <5 mmol/l. CONCLUSIONS: Despite the high prevalence of dyslipidaemia in English adults, the proportion of adults taking lipid lowering drugs in 1998 was only 2.2%. Rates of treatment were low among high risk patients eligible for primary prevention with lipid lowering drugs, and less than one third of patients with established cardiovascular disease received such treatment.

Adolescent↗
PubMed1992

Lipid A activation of glomerular mesangial cells: mimicry of the bioactive lipid, phosphatidic acid.

Lipid A, the active component of bacterial endotoxin, stimulates multiple cell types, including glomerular mesangial cells (MC), and yet the molecular mechanisms of cell activation remain unclear. Lipid A, in its monosaccharyl form, structurally resembles the biologically active lipid phosphatidic acid (PA). Given this, it was postulated that lipid A activates cells by acting as a structural and functional mimetic of PA. Lipid A was found to specifically stimulate an MC lyso-PA acyl transferase activity, leading to enhanced synthesis of sn-2-unsaturated forms of PA. Sn-2-unsaturated PA itself, in contrast to sn-2-saturated PA, also stimulated the lyso-PA acyl transferase activity, a positive feedback feature previously noted with lyso-lecithin acyl transferase. Structure-function correlations demonstrated that the phosphate moieties in both PA and lipid A were necessary to feedback stimulation of lyso-PA acyl transferase (AT), as dephosphorylated lipid A and 2-unsaturated 1,2-sn-diacylglycerol had no stimulatory effect on lyso-PA AT. The biologic relevance of the lipid A and PA-mediated increases in lyso-PA acyl transferase activity was shown, whereby limited exposure to these lipids rapidly induced identical MC morphologic and functional alterations characteristic of cellular activation. By mimicking the stimulatory action of PA, per se, on lyso-PA acyl transferase activity, lipid A may initiate a positive feedback cycle of acylation, yielding increased amounts of PA enriched in unsaturated fatty acids. This newly synthesized PA may subsequently act as the proximal mediator of cellular activation.

Acyltransferases↗