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PubMed1985

Isolation, barrier properties and lipid analysis of stratum compactum, a discrete region of the stratum corneum.

We have isolated the lowest region of human and pig stratum corneum as an integral layer which we have termed the stratum compactum. This preparation is resistant to disruption by enzymes, 6 M urea, Triton X-100 and solvents. Our evidence suggests that all cells of the stratum corneum may be equally permeable to aqueous soluble materials but that penetration of materials through the corneum depends on the state of cohesion between cells and of the organization of intercellular lipid species. As the cells move up towards the outside of the stratum corneum the cohesive forces are reduced due to desmosome degradation and lipid modifications with ultimate dyshesion and sloughing of individual cells.

Animals↗
PubMed2002

Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling.

Hedgehog (Hh) signaling plays a major role in multiple aspects of embryonic development, which involves both short- and long-range signaling from localized Hh sources. One unusual aspect of Hh signaling is the autoproteolytic processing of Hh followed by lipid modification. As a consequence, the N-terminal fragment of Hh becomes membrane anchored on the cell surface of Hh-producing cells. A key issue in Hh signaling is to understand the molecular mechanisms by which lipid-modified Hh protein is transported from its sites of synthesis and subsequently moves through the morphogenetic field. The dispatched gene, which encodes a putative multipass membrane protein, was initially identified in Drosophila and is required in Hh-producing cells, where it facilitates the transport of cholesterol-modified Hh. We report the identification of the mouse dispatched (Disp) gene and a phenotypic analysis of Disp mutant mice. Disp-null mice phenocopy mice deficient in the smoothened gene, an essential component for Hh reception, suggesting that Disp is essential for Hh signaling. This conclusion was further supported by a detailed molecular analysis of Disp knockout mice, which exhibit defects characteristic of loss of Hh signaling. We also provide evidence that Disp is not required for Hh protein synthesis or processing, but rather for the movement of Hh protein from its sites of synthesis in mice. Taken together, our results reveal a conserved mechanism of Hh protein movement in Hh-producing cells that is essential for proper Hh signaling.

Alleles↗
PubMed2005

Production of a recombinant bacterial lipoprotein in higher plant chloroplasts.

Little is known about the potential of plastids to accomplish post-translational modifications of foreign proteins. In the present study we generated transplastomic tobacco plants that accumulate the outer surface lipoprotein A (OspA)-the basic constituent of the first generation monovalent human vaccine against Lyme disease. The recombinant OspA exhibits a lipid modification typical for bacteria and induced protective antibodies in mice, demonstrating that functionally active bacterial lipoproteins can be processed in plants.

Antigens, Surface↗
PubMed2000

Simvastatin, capillary permeability, and acetylcholine-mediated vasomotion in atherosclerotic, hypercholesterolemic men.

OBJECTIVES: The aim of this study was to test the effect of high-dose simvastatin therapy on vascular permeability, a key variable in the atherogenic process, and endothelial-mediated vasodilator responses in patients with hypercholesterolemic atherosclerosis. METHODS: The transcapillary albumin escape rate (TERalb, the 1-hour decline rate of intravenous 125I-albumin, a measure of macromolecular permeability of capillary endothelium) and forearm vasodilatation (venous plethysmography) to intraarterial acetylcholine and sodium nitroprusside (7.5, 15, 30 microg/min and 0.8, 1.6, and 3.2 microg/min respectively, 5 minutes at each rate) to account for endothelium-dependent and independent mechanisms, were measured at baseline and after 1-month simvastatin (40 mg once daily) in 16 hypercholesterolemic (low-density lipoprotein cholesterol >130 mg/dL), atherosclerotic men. Thirteen healthy, untreated subjects were the controls. RESULTS: Baseline TERalb was higher and responsiveness to both acetylcholine and sodium nitroprusside was depressed in patients compared with controls. One-month high-dose simvastatin reduced low-density lipoprotein cholesterol by 39%, normalized TERalb, and improved local vasomotor responses to acetylcholine, without modifying those to sodium nitroprusside. Changes in TERalb and acetylcholine-mediated vasodilatation were dissociated and unrelated to lipid modifications. CONCLUSIONS: Low-density lipoprotein cholesterol reduction through 1 month of high-dose simvastatin normalized the exaggerated transvascular albumin leakage of patients with hypercholesterolemic atherosclerosis, perhaps by restoring an exaggerated endothelial permeability, apparently through mechanisms independent of circulating lipids. Improvements in acetylcholine-mediated vasomotion were also evident, but were dissociated from TERalb, demonstrating a heterogeneous behavior of the 2 indices of endothelial function in response to high-dose statin treatment.

Acetylcholine↗
PubMed2007

Characterization of novel mixed polyethyleneglycol modified liposomes.

In our previous paper, mixed polyetheleneglycol (PEG) modification of liposomes by a mixture of 1-monomethoxypolyethyleneglycol-2,3-distearoylglycerol (PEG-DSG) with short polyoxyethylene chain and PEG-DSG with long one was shown to increase fixed aqueous layer thickness (FALT) around the liposomal membrane, and this was useful in vivo. In this study, we investigated the characterization of mixed PEG modification of liposomes with different anchors (PEG2000-DSG and PEG2000-cholesterol (CHO)). When the liposomes was modified by a mixture of PEG2000-DSG and PEG2000-CHO, FALT was increased compared to that of each single PEG-lipids modification and the most suitable mix modification (PEG2000-DSG:PEG2000-CHO = 3:1) showed a maximum FALT. This phenomenon was speculated to be based on the difference in the insertion state of the PEG anchor unit in the liposomal membrane. PEG-CHO-modified liposomes (single or mixed PEG-modified liposomes) were easily incorporated into the liposomal membranes compared with that of single PEG-DSG-modified liposomes. Namely, it was considered that the cholesterol anchor as a single chain was able to be easily introduced, compared with the DSG anchor as two chains, and induced some interaction with both PEG modification. In conclusion, it is expected that novel PEG-modified liposomes with PEG2000-DSG and PEG2000-CHO (3:1) had superior physicochemical properties.

Cholesterol↗
PubMed1990

A recombinant non-fatty acylated form of the Hi-PAL (P6) protein of Haemophilus influenzae elicits biologically active antibody against both nontypeable and type b H. influenzae.

An approximately 15,000-dalton outer membrane lipoprotein of Haemophilus influenzae, the Hi-PAL (P6) protein, has been shown to elicit bactericidal and protective antibodies against both type b and nontypeable H. influenzae strains and is a vaccine candidate for these organisms. To determine whether the lipid modification of this protein is required for immunogenicity or the elicitation of biologically active antibodies, a genetic fusion was constructed that contains the sequence of mature Hi-PAL fused to the polylinker region of pUC19. The protein expressed by this clone does not contain detectable lipid and was purified to homogeneity. This recombinant fusion protein, rPAL, elicited a strong immune response when injected into rabbits, and the antiserum reacted well with native Hi-PAL. The antiserum was bactericidal against a number of clinical nontypeable strains, duplicating the activity of anti-Hi-PAL. The anti-rPAL antiserum was also protective against type b bacteremia in the infant rat model. These results demonstrate that purified rPAL elicits antibodies with biological activities that are similar to those of anti-Hi-PAL antibodies. Thus, the lipid component of Hi-PAL is not required for either immunogenicity or elicitation of biologically active antibodies.

Acylation↗
PubMed1996

[The effect of total estrogens and lactogen hormone on lipid metabolism in women during normal pregnancy].

Lipids parameters and total oestrogen and HPL levels were estimated in blood serum. Investigated group consisted of 45 women with uneventful course of pregnancy. All pregnant women were in the gestational age between 29 and 40 weeks. This is positive correlation increased concentration of total lipids, LDL fraction, phospholipids, triglycerids and raising of total oestrogens. High concentration of total cholesterol, LDL cholesterol fraction and phospholipids were observed at the same time as increased levels of HPL. We suggest that multivariative hormonal changes during uncomplicated course of gestation could be the cause of modificated lipids profile.

Adult↗
PubMed1999

Effect of ppGpp on Escherichia coli cyclopropane fatty acid synthesis is mediated through the RpoS sigma factor (sigmaS).

Strains of Escherichia coli carrying mutations at the relA locus are deficient in cyclopropane fatty acid (CFA) synthesis, a phospholipid modification that occurs as cultures enter stationary phase. RelA protein catalyzes the synthesis of guanosine-3',5'-bisdiphosphate (ppGpp); therefore, ppGpp was a putative direct regulator of CFA synthesis. The nucleotide could act by increasing either the activity or the amount of CFA synthase, the enzyme catalyzing the lipid modification. We report that the effect of RelA on CFA synthesis is indirect. In vitro and in vivo experiments show no direct interaction between ppGpp and CFA synthase activity. The relA effect is due to ppGpp-engendered stimulation of the synthesis of the alternative sigma factor, RpoS, which is required for function of one of the two promoters responsible for expression of CFA synthase.

Bacterial Proteins↗
PubMed1990

Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation.

Oncogenic forms of ras proteins are synthesized in the cytosol and must become membrane associated to cause malignant transformation. Palmitic acid and an isoprenoid (farnesol) intermediate in cholesterol biosynthesis are attached to separate cysteine residues near the C termini of H-ras, N-ras, and Kirsten-ras (K-ras) exon 4A-encoded proteins. These lipid modifications have been suggested to promote or stabilize the association of ras proteins with membranes. Because preventing isoprenylation also prevents palmitoylation, examining the importance of isoprenylation alone has not been possible. However, the oncogenic human [Val12]K-ras 4B protein is not palmitoylated but is isoprenylated, membrane associated, and fully transforming. We therefore constructed mutant [Val12]K-ras 4B proteins that were not isoprenylated to examine the effects of isoprenylation in the absence of palmitoylation. The nonisoprenylated mutant proteins both failed to associate with membranes and did not transform NIH 3T3 cells. In addition, inhibition of isoprenoid and cholesterol synthesis with the drug compactin also decreased [Val12]K-ras 4B protein isoprenylation and membrane association. These results unequivocally demonstrate that isoprenylation, rather than palmitoylation, is essential for ras membrane binding and ras transforming activity. These findings clearly indicate the biological significance of ras protein modification by farnesol and suggest that this modification may be important for facilitating the processing, trafficking, and biological activity of other isoprenylated proteins. Because K-ras is the most frequently activated oncogene in a wide spectrum of human malignancies, study of this pathway could lead to important therapeutic treatments.

Animals↗
PubMed1989

Use of an expanded-whole-wheat product in the reduction of body weight and serum lipids in obese females.

To achieve weight reduction and alter serum lipid profiles, an air-expanded whole-wheat protein product (SNW) was used by moderately obese women as a meal substitute for 12 wk. Results were compared with those from a standard low-calorie diet (LCD). The SNW group lost 3.9 kg (means) over the first 6 wk and a further 1.6 kg between weeks 6 and 12. In contrast, the LCD group lost 2.8 kg during the initial 6 wk but failed to achieve weight loss during the second 6 wk. Consequently, the SNW group lost nearly twice as much weight over the 12-wk period as did LCD participants. A beneficial effect of SNW on serum cholesterol and triglycerides was noted; both measures declined in conjunction with the weight loss. Such alterations were greater in the SNW group than in LCD participants. Both schemes proved safe. SNW is safe and effective in weight reduction and serum lipid modification in moderately obese women.

Adult↗
PubMed2003

Facing extremes: archaeal surface-layer (glyco)proteins.

Archaea are best known in their capacities as extremophiles, i.e. micro-organisms able to thrive in some of the most drastic environments on Earth. The protein-based surface layer that envelopes many archaeal strains must thus correctly assemble and maintain its structural integrity in the face of the physical challenges associated with, for instance, life in high salinity, at elevated temperatures or in acidic surroundings. Study of archaeal surface-layer (glyco)proteins has thus offered insight into the strategies employed by these proteins to survive direct contact with extreme environments, yet has also served to elucidate other aspects of archaeal protein biosynthesis, including glycosylation, lipid modification and protein export. In this mini-review, recent advances in the study of archaeal surface-layer (glyco)proteins are discussed.

Adaptation, Physiological↗
PubMed1991

Heightened susceptibility of fish oil polyunsaturate-enriched neoplastic cells to ethane generation during lipid peroxidation.

We have studied the generation of volatile hydrocarbons by fatty acid-modified L1210 leukemia cells in tissue culture as a measure of lipid peroxidation. There was considerable generation of ethane, and this was dependent on cell number and Fe2+ concentration; it was eliminated by antioxidants and augmented by ascorbic acid. The assay was sensitive and reproducible; ethane was detected when as little as 0.03% of the cellular n-3 (omega-3) fatty acids were peroxidized. To gain further understanding we used a lipid modification model that allows study of cells enriched with fatty acids of different degrees of unsaturation. The quantity of ethane generated was greatest by cells modified with fatty acids of the n-3 family, and there was a high direct correlation of percentage of n-3 fatty acids contained in cellular lipids with peroxidation as measured by ethane generation. Ethane generation was more sensitive in detecting peroxidation than loss of polyunsaturated fatty acids. We conclude that lipid-supplemented leukemic cells produce ethane, and that the rate of generation is a sensitive, quantitative, and highly useful measure of lipid peroxidation when small amounts of iron are present.

Animals↗
PubMed1998

Clinical trials and external validity.

Although a number of clinical trials are available estimating the benefits of lipid-lowering therapies that include economic end-points, development of modeling methodologies are essential to extend results of those trials over time and to other populations. We reviewed the key issues to be considered when extending trial data to real-world situations. The availability of recent randomized controlled trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in primary and secondary prevention has demonstrated the limitations of earlier modeling efforts to project benefits of lipid modification. The importance of risk stratification is demonstrated, particularly the importance of both LDL and HDL cholesterol either together or as a ratio measure. The selection of modeling methodology to extend benefits of a treatment beyond the end of a trial and over a lifetime is discussed. The relationship between benefits from lipid reduction and risk difference is described, demonstrating that for individuals with established coronary heart disease (CHD) and those older than age 58, benefits from lipid reduction are greater than those predicted from baseline lipid-related risk differences alone. The implications of these data for primary prevention of CHD in the elderly are discussed.

Journal Article↗
PubMed1993

Iron-hydroxamate uptake systems in Bacillus subtilis: identification of a lipoprotein as part of a binding protein-dependent transport system.

Bacillus subtilis was shown to utilize three types of hydroxamate siderophores, ferrichromes, ferrioxamines and shizokinen, each of which is taken up by different transport systems. Mutants deficient in the uptake of ferrichrome and/or ferrioxamine B were isolated. The gene fhuD, which was able to complement a mutant defective in ferrichrome uptake, was cloned. The deduced sequence of FhuD showed low but significant homology to the binding proteins FepB, FecB and FhuD of Escherichia coli, which are all components of binding protein-dependent, ferric siderophore transport systems. The first 23 amino acids of FhuD of B. subtilis possessed all characteristics of a lipoprotein signal sequence. The processing of FhuD in E. coli was inhibited by globomycin. Inhibition by globomycin indicated a lipid modification at the N-terminal cysteine in E. coli. It is highly likely that this step may also take place in B. subtilis. As in other binding protein-dependent transport systems of Gram-positive organisms it is proposed that the lack of a periplasm is compensated for by the lipid through which the binding protein is anchored to the cytoplasmic membrane.

Amino Acid Sequence↗
PubMed2006

Reversible inactivation of the transcriptional function of P53 protein by farnesylation.

BACKGROUND: The use of integrating viral vectors in Gene therapy clinical trials has pointed out the problem of the deleterous effect of the integration of the ectopic gene to the cellular genome and the safety of this strategy. We proposed here a way to induce the death of gene modified cells upon request by acting on a pro-apoptotic protein cellular localization and on the activation of its apoptotic function. RESULTS: We constructed an adenoviral vector coding a chimeric p53 protein by fusing p53 sequence with the 21 COOH term amino acids sequence of H-Ras. Indeed, the translation products of Ras genes are cytosolic proteins that become secondarily associated with membranes through a series of post-translational modifications initiated by a CAAX motif present at the C terminus of Ras proteins. The chimeric p53HRCaax protein was farnesylated efficiently in transduced human osteosarcoma p53-/- cell line. The farnesylated form of p53 resided mainly in the cytosol, where it is non-functional. Farnesyl transferase inhibitors (FTIs) specifically inhibited farnesyl isoprenoid lipid modification of proteins. Following treatment of the cells with an FTI, p53HRCaax underwent translocation into the nucleus where it retained transcription factor activity. Shifting p53 into the nucleus resulted in the induction of p21waf1/CIP1 and Bax transcription, cell growth arrest, caspase activation and apoptosis. CONCLUSION: Artificial protein farnesylation impaired the transcriptional activity of p53. This could be prevented by Farnesyl transferase inhibition. These data highlight the fact that the artificial prenylation of proteins provides a novel system for controlling the function of a transactivating factor.

Adenoviridae↗
PubMedDate not supplied

Atherogenic lipoprotein phenotype in type 2 diabetes: reversal with micronised fenofibrate.

BACKGROUND: To assess the short-term effects of a micronised formulation of fenofibrate on lipids, lipoproteins and their composition, reflecting an atherogenic lipoprotein phenotype (ALP), in patients with stable Type 2 diabetes. METHODS: Thirty-two (18 male, 14 female) patients with Type 2 diabetes were randomised to a double-blind, placebo-controlled parallel group study after a 4-week diet run-in phase to a 12-week treatment period with either daily micronised fenofibrate 200 mg (Lipantil Micro((R))) or placebo. RESULTS: Baseline mean lipid and lipoproteins were similar in both groups: total cholesterol (TC) 7.5 mmol/l, serum triglyceride (TG) 3. 1 mmol/l, HDL-cholesterol (HDL-c) 1.2 mmol/l, LDL-cholesterol (LDL-c) 4.7 mmol/l, and a predominance (52%) of small dense LDL-III at concentration of 192 mg lipoprotein/100 ml, reflecting an ALP. Treatment with micronised fenofibrate resulted in significant changes in TC (-17%, p<0.001), serum TG (-44%, p<0.05), HDL-c (+20%, p<0.01), LDL-c (-22%, p<0.001), apo-B (-18%, p<0.05) and alterations in LDL subfraction masses (LDL-I +64%, p<0.05; LDL-II +53%, p<0.05; LDL-III -51%, p<0.001) resulting in LDL-III comprising 28% of total LDL (p<0.001). In the placebo group the only significant changes were in TG (+21%, p<0.05) and apo-B (+9%, p<0.05). CONCLUSIONS: Micronised fenofibrate therapy in patients with Type 2 diabetes improved an establisheded ALP resulting in a more favourable lipid and LDL subfraction profile. The long-term clinical implications of these changes await the results of the major intervention trials of lipid modification in Type 2 diabetes.

Adult↗
PubMed1998

Chain length and temperature dependence of the reversible association of model acylated proteins with lipid bilayers.

To study the binding of fatty-acylated proteins to lipid bilayers, we have specifically attached fatty acids to the N-terminus of chemically modified bovine pancreatic trypsin inhibitor. This was accomplished by reacting the protein with saturated fatty acid anhydrides ranging in length from 8 to 18 carbons. Following radiolabeling of the fatty-acylated proteins at Lys-15, binding of these proteins to palmitoyloleoyl phosphatidylcholine vesicles was examined as a function of temperature using ultracentrifugation to determine the fraction of bound protein. Binding of these fatty-acylated proteins exhibited a significant enthalpy change. We also examined the free-energy change of binding as a function of fatty acid chain length. Our results are complimentary to other binding studies of fatty-acylated peptides. Comparisons with other myristoylated proteins and peptides indicate that local protein structure, apart from electrostatic interactions, plays a significant role in determining the magnitude of the overall free-energy change of membrane binding of fatty-acylated proteins. Light-scattering experiments indicated that both myristoyl and palmitoyl groups can induce protein micelle formation in aqueous solution at high concentration, but that only palmitoyl groups do so at physiologically relevant concentrations. Our results support a model in which single lipid modifications are incapable of stably anchoring proteins to biological membranes but facilitate protein associations in conjunction with other modes of interaction.

Acylation↗
PubMed1999

Synthesis of the palmitoylated and prenylated C-terminal lipopeptides of the human R- and N-Ras proteins.

For the study of biological phenomena influenced by the R- and N-Ras proteins, characteristic peptides which embody the correct lipid modifications of their parent proteins (palmitoyl thioesters, geranylgeranyl thioethers, and farnesyl thioethers), as well as analogues thereof, may serve as efficient tools. For the construction of such acid- and base labile peptide conjugates the allyl ester was developed as C-terminal protecting group. Allyl esters are cleaved selectively and in high yields from lipidated peptides by Pd(0)-mediated allyl transfer to accepting N- or C-nucleophiles like morpholine and N,N'-dimethylbarbituric acid. This protecting group technique formed the key step in the synthesis of the characteristic S-palmitoylated and S-isoprenylated C-terminus of human R-Ras and human N-Ras proteins, as well as several analogues thereof. Deprotections are so mild that no undesired side reactions of the lipid conjugates are observed.

Humans↗