Disease relevance of lipid X

• In our work, this is best illustrated by the analysis of phosphatidylglycerol-deficient mutants of E. coli, which provided the clue (i.e. lipid X) that permitted the elucidation of lipid A biosynthesis [1].
• Lipid X appears to have a novel mechanism of inhibiting LPS effect and may have efficacy in the treatment of gram-negative sepsis [2].
• This inhibition was not due to cellular toxicity, the phospholipidlike nature of lipid X, interference with the PAI-2 assay, or monocyte production of a substance interfering with PAI-2 [3].
• Lipid A synthase from Salmonella accepts not only lipid X but also the synthetic di-N-acyl-2,3-diamino-D-glucose analogue as substrate (Raetz, C.R.H., unpublished results) [4].
• LBP was found to bind to a variety of LPS types from both rough and smooth strains of Gram-negative bacteria, to lipid A, and to the tetraacyl glucosamine disaccharide diphosphate precursor IVA, but bound very poorly to the diacyl glucosamine phosphate, lipid X [5].

Psychiatry related information on lipid X

• Intracerebroventricular, but not intravenous, injections of lipid X induced small but significant increases in both slow-wave sleep and rapid-eye-movement sleep without affecting delta amplitudes or brain-colonic temperatures [6].

High impact information on lipid X

• In contrast, MPLA, lipid X, and deacylated LPS failed to inhibit LPS-stimulated release of TNF [7].
• Although lipid X inhibited thrombin-induced phosphorylation of P47 it did not suppress secretion of [14C]serotonin, indicating the role of protein kinase C-independent pathways in platelet stimulation by thrombin [8].
• Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-lipid X [2].
• Although PagL is most likely active as a monomer, its active site architecture shows high resemblance to that of the dimeric 12-stranded outer membrane phospholipase A. Modeling of the substrate lipid X onto the active site reveals that the 3-O-acyl chain is accommodated in a hydrophobic groove perpendicular to the membrane plane [9].
• If lipid X and lipid A induce by common mechanism(s) B-lymphocyte proliferation, then it follows from structural comparison that the reducing-end subunit of lipid A is the minimal structural requirement for this activity [10].

Chemical compound and disease context of lipid X

• Previous studies from our laboratory have documented the presence in vivo of the precursors 2,3-diacylglucosamine 1-phosphate (2,3-diacyl-GlcN-1-P) (lipid X of E. coli) and UDP-2,3-diacylglucosamine (UDP-2,3-diacyl-GlcN) (Bulawa, C.E., and Raetz, C.R.H.J. Biol. Chem. 259, 4846-4851) [11].
• Mitogenic and PBA activity of GLA-27 were stronger than those of lipid X, which corresponds to the reducing D-GlcN (GlcN-I) subunit of Escherichia coli lipid A and is a 1-O-phosphorylated GlcN derivative carrying N- and 3-O-linked C14OH groups [12].
• The effects of lipid X and 3-aza-lipid X on in vitro neutrophil function were related to their ability to inhibit the toxicity of endotoxin in galactosamine-sensitized mice [13].
• Pulmonary oxygen toxicity in rats: prevention by pyrogenic diphosphoryl lipid A and potentiation by nontoxic monophosphoryl lipid A and lipid X [14].

Biological context of lipid X

• These results suggest that lipid X, a compound structurally related to lipid A, may block neutrophil priming by competing with LPS for cellular binding sites [2].
• The lipid moieties of lipid X are heterogenous in that about 50% of headgroups remain bound to a lipid moiety after mild alkaline hydrolysis [15].
• Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep [16].
• The pharmacokinetics described here should greatly aid in the design and interpretation of animal studies investigating the therapeutic applications of lipid X in gram-negative septicemia [16].
• However, like endotoxin, lipid X also produced a late phase (3-6 h later) of increased lung vascular permeability to fluid and protein as reflected by significant (P less than 0.05) increases in both lung-lymph flow and lung-lymph protein clearance in the presence of stable pulmonary vascular pressures at or below base-line levels [17].

Anatomical context of lipid X

• Increasing concentrations of lipid X shifted the LPS dose response curve of neutrophils rightward but did not prevent maximum priming at higher LPS concentrations, a finding consistent with competitive inhibition [2].
• We have examined the activity of lipid X (Mr = 711.9) and several related compounds as mitogens towards mouse lymphocytes [10].
• Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X [3].
• Lipid X, on the other hand, was incapable of making macrophages hyporesponsive for TNF production [18].
• A monosaccharide precursor of Escherichia coli lipid A, designated lipid X, which is a diacylglucosamine 1-phosphate with beta-hydroxymyristoyl groups at positions 2 and 3, was shown to have the ability to induce the production of tumor necrosis factor (TNF)-like tumor-cytotoxic factor by a murine macrophage-like cell line, J774 [19].

Associations of lipid X with other chemical compounds

• Unlike the disaccharide inhibitors, PMN exposed to lipid X were still responsive to LPS stimulation after washing [20].
• Precursors of the lipid portion of LPS (lipid X and lipid Y), LPS isolated by trichloroacetic acid extraction, and endotoxin-associated protein (EAP) increased C3 and factor B synthesis in cord blood monocytes [21].
• Lipid X appears to accumulate mainly in the liver, and the tissue distribution of lipid X resembles that of lipopolysaccharide [16].
• Survival of CD16-negatively selected eosinophils was enhanced by LPS in a dose-dependent manner and was inhibited by the endotoxin antagonists polymyxin B or lipid X [22].
• These studies strongly indicate that lipid Y is a member of the protein anchor class of glycosylphosphatidylinositol, whereas lipid X is a member of the signal transduction inositol phosphoglycan class of glycosylphosphatidylinositol [23].

Gene context of lipid X

• Lipid X was an effective inhibitor of PAI-2 production even when added up to 30 minutes after LPS [3].
• The monosaccharide lipid A precursor lipid X also blocked stimulation of neutrophils by LPS, although with a 100-fold reduction in potency [20].
• Pretreatment of macrophages with IFN-gamma resulted in the release of higher amounts of TNF on subsequent induction with either LPS or lipid X [18].
• These data suggest the involvement of a GTPase in LPS action, and indicate that lipid X may act to directly antagonize LPS at this level [24].
• However, recent work shows that synthetic lipid X can be contaminated with small amounts of N,O-acylated disaccharide-1-phosphate (H. Aschauer, A. Grob, J. Hildebrandt, E. Schuetze, and P. Steutz, J. Biol. Chem. 265:9159-9164, 1990) [25].

Analytical, diagnostic and therapeutic context of lipid X

• Lipid X is a novel agent that enhances survival in an animal model of severe infection with gram-negative organisms [26].
• Lipid X is a potential prototype compound for a new type of chemotherapy directed at blocking the harmful effects of LPS during bacterial septicemia [27].
• Intravenous infusion of lipid X in goats had no effect except for a modest elevation in the pulmonary artery pressure during the period of infusion [28].
• Group 1 heifers (n = 3) received 5 micrograms kg-1 bodyweight of Escherichia coli endotoxin as an intrauterine infusion and one hour later received an intravenous injection of lipid X (5 micrograms kg-1 bodyweight) [29].

References