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PubMed1997

Cholesterol management in theory and practice.

The preponderance of evidence confirms the importance of aggressive lipid modification in patients at risk for coronary heart disease (CHD). However, data suggest that this information is underimplemented in the clinical setting, even in patients with existing CHD, in whom the greatest benefit of such treatment has been shown. The fact that many practitioners do not pursue a proven treatment strategy in patients who qualify must be redressed through education and reinforcement of existing recommendations. In the present review, the current clinical and mechanistic understanding of the benefit of aggressive lipid management is summarized, with a focus on the clinical implications of recent findings. These include growing public awareness of cholesterol as a modifiable CHD risk factor, recommendations for earlier and more aggressive intervention in patients with existing disease, and discussion of the cost-effectiveness of lipid-regulating therapy. Despite the secular trend of declining CHD morbidity and mortality rates in recent years, CHD remains the leading cause of death in both men and women in the United States. It is imperative to prevent any reduction in public focus on primary and secondary prevention.

Anticholesteremic Agents↗

PubMed1996

Nutritional and metabolic aspects of postprandial lipemia.

The present review deals with the nutritional and metabolic aspects of postprandial lipemia. The postmeal state is characterized by the accumulation of triglyceride-rich lipoproteins (TRL) in the plasma. This is due to the competition for clearance between hepatically-derived very low density lipoproteins (VLDL) and intestinally-derived chylomicrons. At the same time, an important remodeling of the low density lipoprotein (LDL) and high density lipoprotein (HDL) particles takes place. The amplitude and/or time-course of the occurrence of the postprandial triglyceride response is influenced by the quantity of dietary lipids (triglycerides, cholesterol), the fatty acid composition of dietary triglycerides and the amount and nature of dietary carbohydrates and fibers. The preexisting metabolic status of the subjects markedly influences the postprandial response; i.e., hyperlipidemic, diabetic and obese subjects can exhibit an exaggerated increase in triglycerides and lipoprotein remodeling. The hypothesis that postprandial lipid modifications are associated with atheroma deposition and coronary events has been supported by several experimental observations. Despite the significant amount of knowledge already obtained in this field, further research is needed to better elucidate the existing relationships between dietary intake, postprandial response and pathological events.

Arteriosclerosis↗

PubMed2006

Stability of barley and malt lipid transfer protein 1 (LTP1) toward heating and reducing agents: relationships with the brewing process.

Barley lipid transfer protein (LTP1) is a heat-stable and protease-resistant albumin that concentrates in beer, where it participates in the formation and stability of beer foam. Whereas the barley LTP1 does not display any foaming properties, the corresponding beer protein is surface-active. Such an improvement is related to glycation by Maillard reactions on malting, acylation on mashing, and structural unfolding on brewing. The structural stability of purified barley and glycated malt LTP1 toward heating has been analyzed. Whatever the modification, lipid adduction or glycation, barley LTP1s are highly stable proteins that resisted temperatures up to 100 degrees C. Unfolding of LTP1 occurred only when heating was conducted in the presence of a reducing agent. In the presence of sodium sulfite, the lipid-adducted barley and malt LTP1 displayed higher heat stability than the nonadducted protein. Glycation had no or weak effect on heat-induced unfolding. Finally, it was shown that unfolding occurred on wort boiling before fermentation and that the reducing conditions are provided by malt extract.

Beer↗

PubMed2000

RhoA prenylation is required for promotion of cell growth and transformation and cytoskeleton organization but not for induction of serum response element transcription.

The importance of post-translational geranylgeranylation of the GTPase RhoA for its ability to induce cellular proliferation and malignant transformation is not well understood. In this manuscript we demonstrate that geranylgeranylation is required for the proper cellular localization of V14RhoA and for its ability to induce actin stress fiber and focal adhesion formation. Furthermore, V14RhoA geranylgeranylation was also required for suppressing p21(WAF) transcription, promoting cell cycle progression and cellular proliferation. The ability of V14RhoA to induce focus formation and enhance plating efficiency and oncogenic Ras anchorage-dependent growth was also dependent on its geranylgeranylation. The only biological activity of V14RhoA that was not dependent on its prenylation was its ability to induce serum response element transcriptional activity. Furthermore, we demonstrate that a farnesylated form of V14RhoA was also able to bind RhoGDI-1, was able to induce cytoskeleton organization, proliferation, and transformation, and was just as potent as geranylgeranylated V14RhoA at suppressing p21(WAF) transcriptional activity. These results demonstrate that RhoA geranylgeranylation is required for its biological activity and that the nature of the lipid modification is not critical.

3T3 Cells↗

PubMed1993

Lipid-tagged antibodies: bacterial expression and characterization of a lipoprotein-single-chain antibody fusion protein.

In order to achieve a stable and functional immobilization of antibodies, we investigated the possibility of adding hydrophobic membrane anchors to antibody fragments expressed in Escherichia coli. The DNA sequence encoding the signal peptide and the nine N-terminal amino acid residues of the major lipoprotein of E.coli was fused to the sequence of an anti-2-phenyloxazolone single-chain Fv antibody fragment [Takkinen et al. (1991) Protein Engng, 4,837-841]. The expression of the fusion construct in E.coli resulted in specific accumulation of an immunoreactive 28 kDa polypeptide. Unlike the unmodified single-chain Fv fragment, the fusion protein was cell-associated, labelled by [3H]palmitate which is indicative of the presence of N-terminal lipid modification, partitioned into the detergent phase upon Triton X-114 phase separation and was localized predominantly in the bacterial outer membrane. The fusion antibody displayed specific 2-phenyloxazolone-binding activity in the membrane-bound form and after solubilization with non-ionic detergents. Furthermore, upon removal of detergent the fusion antibody was incorporated into proteoliposomes which displayed specific hapten-binding activity. Our results show that antibodies can be converted to membrane-bound proteins with retention of antigen-binding properties by introduction of lipid anchors during biosynthesis. This approach may prove useful in the design of immunoliposomes and immunosensors.

Amino Acid Sequence↗

PubMed1988

Processing by inverted plasma membrane vesicles of in vitro synthesized major lipoprotein from Escherichia coli.

Synthesis, lipid modification and proteolytic processing of the major lipoprotein from Escherichia coli is shown to occur in a homologous in vitro transcription-translation system containing inverted plasma membrane vesicles. The primary translation product (cross-reacting with anti-lipoprotein antiserum) is a precursor which is converted into a lower molecular mass species of the size of mature lipoprotein by the addition of inverted membrane vesicles from E. coli. Conversion is prevented by globomycin, a specific inhibitor of the unique lipoprotein-signal peptidase II, which is active only on lipid-containing precursors. The inverted plasma membrane vesicles used here must therefore contain active lipid-modifying enzymes and signal peptidase II.

Cell Membrane↗

PubMed2001

Solid lipid nanoparticles: production, characterization and applications.

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.

Capsules↗

PubMed1998

Signalling functions of protein palmitoylation.

Covalent lipid modifications anchor numerous signalling proteins to the cytoplasmic face of the plasma membrane. These modifications mediate protein-membrane and protein-protein interactions and are often essential for function. Protein palmitoylation, due to its reversible nature, may be particularly important for modulating protein function during cycles of activation and deactivation. Despite intense investigation, the exact functions of protein palmitoylation are not well understood. However, it is clear that palmitoylation can affect a protein's affinity for membranes, subcellular localization, and interactions with other proteins. In this review, recent advances in understanding the functions and mechanisms of protein palmitoylation are discussed, with particular emphasis on how this lipid affects the biochemistry and cell biology of signalling proteins.

Cell Membrane↗

PubMed1997

KapB is a lipoprotein required for KinB signal transduction and activation of the phosphorelay to sporulation in Bacillus subtilis.

KinB is one of the two major histidine kinases that provide phosphate input in the phosphorelay to produce SpoOA approximately P, the key transcription factor controlling the initiation of sporulation. A search for insertion mutants affected in activation of KinB-dependent sporulation led to the identification of the lgt locus encoding the lipoprotein glyceryltransferase required for the lipid modification of prolipoproteins before their cleavage and translocation across the cytoplasmic membrane. In parallel, a putative lipoprotein signal peptide cleavage site was detected in KapB, known to be strictly required for KinB-mediated sporulation and located downstream of KinB in a single transcription unit. Using PhoA peptide fusions, we have shown that KapB signal-peptide can direct active alkaline phosphatase to the outer surface of the cytoplasmic membrane in an LGT-dependent manner, strongly suggesting that KapB is a lipoprotein tethered to the outer face of the cytoplasmic membrane via a lipid anchor. As KapB proved to be dispensable for expression of the kinBkapB operon, a chimeric kinase was built consisting of KinA sensor domain fused to KinB kinase domain (KinA'-'B) to assess (i) the involvement of KapB in catalysis of the kinase reaction, and (ii) the ability of KinB to phosphorylate SpoOF in vitro. It was shown that KapB is dispensable for both in vivo and in vitro activation of the phosphorelay by the KinA'-'B chimera and that KinA'-'B phosphorylates SpoOF directly in vitro. Models for the role of KapB in regulating KinB activity are discussed.

Alkaline Phosphatase↗

PubMed2003

A plethora of targets, a paucity of drugs: progress towards the development of novel chemotherapies for human African trypanosomiasis.

Human African trypanosomiasis is a major health problem in large regions of Africa. Current chemotherapeutic options are limited and far from ideal. A diverse range of drug targets has been identified and validated in trypanosomes. These include several organelles (glycosomes, acidocalcisomes, kinetoplast) that are not represented in the mammalian host and biochemical pathways that differ significantly from host counterparts (carbohydrate metabolism, protein and lipid modification, response to oxidative stress, cell cycle). However, there has been little progress in developing novel drugs. Pharmaceutical companies are unwilling to invest in the development of drugs for a market that comprises some of the worlds poorest people. This review highlights some of the most attractive drug targets in trypanosomes.

Calcium↗

PubMed2003

Tripalmitoyl-S-glyceryl-cysteine-dependent OspA vaccination of toll-like receptor 2-deficient mice results in effective protection from Borrelia burgdorferi challenge.

Toll-like receptor 2 (TLR2) is a transmembrane signal transducer for tripalmitoyl-S-glyceryl-cysteine (Pam(3)Cys)-modified lipoproteins, including OspA from the Lyme disease spirochete Borrelia burgdorferi. The Pam(3)Cys modification provides adjuvant activity for inducing humoral responses, suggesting that TLR2 could function as the adjuvant receptor for the OspA vaccine. The importance of TLR2 in the humoral response to OspA was confirmed, because overall levels of immunoglobulin G (IgG) were reduced in TLR2-deficient mice, when compared with those in wild-type mice. However, the levels of production of IgG1 were similar in both mouse strains, and the levels of induction of protective immunity were comparable. Unlipidated OspA was not immunogenic in wild-type or TLR2-deficient mice, indicating the lipid modification was active in the absence of TLR2. These findings indicate that the Pam(3)Cys modification of bacterial lipoprotein has adjuvant properties independent of TLR2 signaling.

Animals↗

PubMed2006

Aberrant receptor-mediated endocytosis of Schistosoma mansoni glycoproteins on host lipoproteins.

BACKGROUND: Bilharzia is one of the major parasitic infections affecting the public health and socioeconomic circumstances in (sub) tropical areas. Its causative agents are schistosomes. Since these worms remain in their host for decades, they have developed mechanisms to evade or resist the immune system. Like several other parasites, their surface membranes are coated with a protective layer of glycoproteins that are anchored by a lipid modification. METHODS AND FINDINGS: We studied the release of glycosyl-phosphatidylinositol (GPI)-anchored proteins of S. mansoni and found them in the circulation associated with host lipoprotein particles. Host cells endocytosed schistosomal GPI-anchored proteins via their lipoprotein receptor pathway, resulting in disturbed lysosome morphology. In patients suffering from chronic schistosomiasis, antibodies attacked the parasite GPI-anchored glycoproteins that were associated with the patients' own lipoprotein particles. These immunocomplexes were endocytosed by cells carrying an immunoglobulin-Fc receptor, leading to clearance of lipoproteins by the immune system. As a consequence, neutral lipids accumulated in neutrophils of infected hamsters and in human neutrophils incubated with patient serum, and this accumulation was associated with apoptosis and reduced neutrophil viability. Also, Trypanosoma brucei, the parasite that causes sleeping sickness, released its major GPI-anchored glycoprotein VSG221 on lipoprotein particles, demonstrating that this process is generalizable to other pathogens/parasites. CONCLUSIONS: Transfer of parasite antigens to host cells via host lipoproteins disrupts lipid homeostasis in immune cells, promotes neutrophil apoptosis, may result in aberrant antigen presentation in host cells, and thus cause an inefficient immune response against the pathogen.

Animals↗

PubMed1992

Women in the POSCH trial. Effects of aggressive cholesterol modification in women with coronary heart disease. The POSCH Group. Program on the Surgical Control of the Hyperlipidemias.

The Program on the Surgical Control of the Hyperlipidemias (POSCH) provided the clearest and the most convincing evidence supporting the beneficial effects of cholesterol lowering in hypercholesterolemic survivors of a myocardial infarction. In POSCH, 78 of the 838 patients (9.3%) were women, with 32 randomized to the diet-control group and 46 to the diet plus partial ileal bypass surgery-intervention group. At 5 years, the mean per cent change from baseline was -23.9% for total plasma cholesterol (p < 0.0001), -36.1% for low-density lipoprotein cholesterol (p < 0.0001), and +8.5% for high-density lipoprotein cholesterol (p = not significant). Because of the small number of women, no statistically significant changes in clinical event rates were observed between the control and the surgery groups. A comparison of 162 coronary arteriography film pairs in the POSCH women, between baseline and 3, 5, 7, and 10 years, consistently showed less disease progression in the surgery group (p = 0.013 for combined assessments of the baseline to the longest follow-up film). Because the lipid and coronary arteriography findings in the POSCH women paralleled these findings in the total POSCH population and in the POSCH men, and because the arteriography changes in POSCH have previously been demonstrated to be statistically significant surrogate end points for certain clinical events and predictors of overall and atherosclerotic coronary heart disease mortality rates, we conclude that the lipid modification achieved in the POSCH women by partial ileal bypass reduced their atherosclerosis progression. The POSCH findings in women support the aggressive treatment of hyperlipidemia in the general management of atherosclerosis in women.

Coronary Angiography↗

PubMed1991

The G protein connection: molecular basis of membrane association.

Two distinct types of lipid modification, myristoylation and isoprenylation, are critical for membrane association of heterotrimeric G proteins. Elucidation of the molecular basis for G protein membrane association has important implications for understanding G protein structure and function, and is relevant to potential therapeutic approaches to AIDS and cancer.

Amino Acid Sequence↗

PubMed2005

The TIP GROWTH DEFECTIVE1 S-acyl transferase regulates plant cell growth in Arabidopsis.

TIP GROWTH DEFECTIVE1 (TIP1) of Arabidopsis thaliana affects cell growth throughout the plant and has a particularly strong effect on root hair growth. We have identified TIP1 by map-based cloning and complementation of the mutant phenotype. TIP1 encodes an ankyrin repeat protein with a DHHC Cys-rich domain that is expressed in roots, leaves, inflorescence stems, and floral tissue. Two homologues of TIP1 in yeast (Saccharomyces cerevisiae) and human (Homo sapiens) have been shown to have S-acyl transferase (also known as palmitoyl transferase) activity. S-acylation is a reversible hydrophobic protein modification that offers swift, flexible control of protein hydrophobicity and affects protein association with membranes, signal transduction, and vesicle trafficking within cells. We show that TIP1 binds the acyl group palmitate, that it can rescue the morphological, temperature sensitivity, and yeast casein kinase2 localization defects of the yeast S-acyl transferase mutant akr1Delta, and that inhibition of acylation in wild-type Arabidopsis roots reproduces the Tip1- mutant phenotype. Our results demonstrate that S-acylation is essential for normal plant cell growth and identify a plant S-acyl transferase, an essential research tool if we are to understand how this important, reversible lipid modification operates in plant cells.

Acyltransferases↗

PubMed2006

How does cholesterol affect the way Hedgehog works?

Members of the Hedgehog (Hh) family of proteins are conserved morphogens that spread and modulate cell fates in target tissue. Mature Hh carries two lipid adducts, a palmitoyl group at the N terminus and cholesterol at the C terminus. Recent findings have addressed how these lipid modifications affect the function and transport of Hh in Drosophila. In contrast to the palmitoyl adduct, cholesterol appears not to be essential for signalling. However, the absence of the cholesterol adduct affects the spread of Hh within tissues. As we discuss here, the exact nature of this effect is controversial.

Animals↗

PubMed2002

Low- and high-density lipoprotein cholesterol and ischemic cerebrovascular disease: the bezafibrate infarction prevention registry.

BACKGROUND: Despite increasing evidence that beta-hydroxy-beta-methyglutaryl coenzyme A reductase inhibitors reduce the incidence of stroke in patients with coronary heart disease (CHD), the associations between blood lipid levels and cerebrovascular disease (CVD) are not clear. OBJECTIVE: To evaluate whether blood cholesterol level and its fractions are risk factors for stroke in a large group of patients with CHD. METHODS: We followed up 11 177 patients with documented CHD who were screened for but not included in the Bezafibrate Infarction Prevention study, a secondary prevention randomized clinical trial of lipid modification, and had no history of stroke for subsequent CVD. During a 6- to 8-year follow-up period, 941 patients were identified as having nonhemorrhagic CVD, of whom 487 had verified ischemic stroke or transient ischemic attack (TIA). RESULTS: Increases in age-adjusted rates of both nonhemorrhagic CVD and verified ischemic stroke or TIA were identified with increasing cholesterol and low-density lipoprotein cholesterol levels, decreasing high-density lipoprotein cholesterol levels, and decreasing percentage of total serum cholesterol contained in the HDL moiety. In logistic regression models, adjusting for clinical covariates, the following odds ratios (95% confidence intervals) were identified for lipid values in the upper vs lower tertile for the end point of nonhemorrhagic CVD: total cholesterol, 1.43 (1.20-1.70); low-density lipoprotein cholesterol, 1.52 (1.27-1.81), high-density lipoprotein cholesterol, 0.84 (0.70-1.00); and percentage of serum cholesterol contained in HDL, 0.69 (0.58-0.83). Similar trends appeared for the end point of verified ischemic stroke or TIA. CONCLUSION: These findings clearly support the role of total cholesterol and its fractions in prediction of ischemic CVD among patients with established CHD.

Adult↗

PubMed1980

Behavior of vesicular stomatitis virus glycoprotein in mouse LM cells with modified membrane-phospholipids.

LM cells in which the membrane phospholipids had been modified with choline analogues were infected with vesicular stomatitis virus. The choline analogues tested were choline, N,N'-dimethylethanolamine, N-monomethylethanolamine and ethanolamine. These modifications per se did not affect the syntheses of individual viral proteins. The viral glycoprotein was detected in the plasma membranes of all the modified cells by pronase digestion in pulse-chase experiments, but the amount of glycoprotein susceptible to proteolysis varied, decreasing in these modified cells in the following order: N,N'-dimethylethanolamine- greater than choline- greater than N-monomethylethanolamine- greater than ethanolamine-treated cells. After a 4-h chase, glycoprotein was mainly distributed in the plasma membranes of cells modified with N,N'-dimethylethanolamine, whereas it was found in both the microsomes and plasma membranes of cells modified with other analogues. Fairly large amounts of glycoprotein were also found in the soluble fraction of ethanolamine-treated cells, but not in that of choline- or N,N'-dimethylethanolamine-treated cells. More precise experiments on the behaviour of glycoprotein with a short period of chase strongly suggested that migration of glycoprotein from the microsomes to the plasma membranes was fastest in cells modified with N,N'-dimethylethanolamine and slowest in cells modified with ethanolamine. Membrane lipid modifications also resulted in release of different numbers of progeny virions from the cells, release of virions from the cells decreasing in the following order: N,N'-dimethylethanolamine- greater than choline- greather N-monomethylethanolamine- greater than ethanolamine-treated cells. These results indicate that modification of membrane phospholipids influences not only the insertion of glycoprotein into the microsomes and its migration to the plasma membranes, but also the production of progeny virions.

Animals↗