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PubMed1984

Lipid associated calcium ionophores in islet cell plasma membrane following glucose stimulation.

The effect of glucose exposure on lipid associated calcium ionophoretic activity was measured in cultured neonatal rat pancreatic islet cells using two model systems. The first measured the ability of a lipid extract of islet cells to facilitate calcium transfer from an aqueous to organic phase and thus detected lipids which transfer calcium in the manner of authentic ionophores or which chelate the ion. In this system glucose stimulation was followed by an increase in total cell ionophoretic activity and a decrease in the activity associated with the plasma membrane. The second system measured the transfer of calcium across an artificial phospholipid membrane and detected authentic ionophoretic activity. In this model an increase in total ionophoretic activity was again seen following glucose but there was no change in the ionophoretic activity of a plasma membrane extract. The results indicate that the lipid modifications which accompany glucose-induced insulin release may alter cellular calcium stores by decreasing lipid bound calcium at the plasma membrane and increasing the capacity for calcium ionophoresis at intracellular sites.

Animals↗
PubMed2006

Trafficking and signaling by fatty-acylated and prenylated proteins.

A wide variety of signaling proteins are modified by covalently linked fatty acids and/or prenyl groups. These hydrophobic moieties, which include myristate, palmitate, farnesyl and geranylgeranyl, are more than just fat: they provide distinct information that modulates the specificity and efficiency of signal transduction. Recent studies show that lipid modification influences the movement of a signaling protein within the cell and its final destination. Protein lipidation can also confer reversible association with membranes and other signaling proteins. These findings provide new insights into the biochemical and biophysical mechanisms that regulate membrane targeting, trafficking and signaling by lipid-modified proteins.

Acylation↗
PubMed2001

Perspectives-- Focus on statins: lipid-lowering mechanisms and beyond.

Recent large-scale clinical trials have confirmed that statin-induced lipid modification can significantly reduce cardiovascular morbidity and mortality. Statins are now the drugs of choice in lipid management but fail to meet the criteria for an ideal therapy in several respects. Therefore, the search continues for lipid modifying treatments that meet even higher standards. Lipid-lowering drugs currently in development may meet these more exacting standards and together with complementary methods could ultimately form ideal combination therapy. (c) 2001 by CHF, Inc.

Journal Article↗
PubMed1998

Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6.

The G protein-coupled receptor kinase GRK6 undergoes posttranslational modification by palmitoylation. Palmitoylated GRK6 is associated with the membrane, while nonpalmitoylated GRK6 remains cytosolic. We have separated palmitoylated from nonpalmitoylated GRK6 to assess their relative kinase activity. Palmitoylated GRK6 is 10-fold more active at phosphorylating beta2-adrenergic receptor than nonpalmitoylated wild-type GRK6 or a nonpalmitoylatable mutant GRK6. A nonpalmitoylatable mutant GRK6 which has been further mutated to undergo posttranslational geranylgeranylation is also more active, recovering most of the activity of the palmitoylated enzyme. This activity increase by lipid modification is expected, as the lipid helps GRK6 localize to cellular membranes where its receptor substrates are found. However, when assayed using a soluble protein (casein) as a substrate, both palmitoylated and prenylated GRK6 display significantly higher activity than nonpalmitoylated wild-type or nonpalmitoylatable mutant GRK6 kinases. This increased activity is not altered by addition of exogenous palmitate or phosphatidycholine vesicles, arguing that it is not due to direct activation of GRK6 by binding palmitate, nor to nonspecific association of the GRK6 with casein. Further, chemical depalmitoylation reduces the casein phosphorylation activity of the palmitoylated, but not prenylated, GRK6 kinase. Thus, palmitoylation of GRK6 appears to play a dual role in increasing the activity of GRK6: it increases the hydrophobicity and membrane association of the GRK6 protein, which helps bring the GRK6 to its membrane-bound substrates, and it increases the kinase catalytic activity of GRK6.

Animals↗
PubMed2006

Prevention of farnesylation of c-Ha-Ras protein enhances synergistically the cytotoxic action of doxorubicin in cycling but not in quiescent cells.

Ras, the product of a proto-oncogene, is a GTP-hydrolyzing enzyme found mutated in approximately 50% of human cancers. "Gain of function" mutations of Ras lead to an escape of transformed cells from cell-cycle control, rendering them independent to stimulation by growth factors, giving them almost unlimited proliferation capacity. The cytosolic precursor isoform of Ras is biologically inactive. After several post-translational modifications, Ras is anchored to the plasma membrane and, thereby, the protein becomes activated. The finding that lipid modifications of Ras protein, particularly farnesylation, are essential for its signal transduction activity, gave rise to the concept that blocking farnesyl protein transferase (FPTase), the enzyme catalyzing the first step in the Ras modification cascade, would prevent proper membrane anchoring and provide an improved approach in the cure of tumors harboring Ras mutations. In the present study we used transformed rat cells overexpressing a temperature-sensitive p53 protein, adopting wt conformation at 32 degrees C and mutant conformation at 37 degrees C. We treated the cells growing at 32 or 37 degrees C with doxorubicin alone, or in combination with inhibitors of FPTase. Combined treatment was more efficient and the same inhibition of cell proliferation was reached at lower DOX concentrations. The treatment strongly affected the growth rate of tumor cells but only negligibly of normal cells. However, the inhibitors of FPTase prevented the membrane anchoring in both situations. These results show two striking advantages of the combined treatment: the desired cytostatic effect on tumor cells at lower drug concentrations and clearly reduced adverse effects on quiescent cells.

Animals↗
PubMed1983

Temperature-induced modifications of glycosphingolipids in plasma membranes of Neurospora crassa.

Plasma membranes isolated from a cell-wall-less mutant of Neurospora crassa grown at 37 and 15 degrees C display large differences in lipid compositions. A free sterol-to-phospholipid ratio of 0.8 was found in 37 degrees C membranes, while 15 degrees C plasma membranes exhibited a ratio of nearly 2.0. Membranes formed under both growth conditions were found to contain glycosphingolipids. Cultures grown at the low temperature, however, were found to contain 6-fold higher levels of glycosphingolipids and a corresponding 2-fold reduction of phospholipid levels. The high glycosphingolipid content at 15 degrees C compensates for the reduced levels of phospholipids in such a way that sterol/polar lipid ratios are almost the same in plasma membranes under the two growth conditions. Temperature-dependent changes in plasma-membrane phospholipid and glycosphingolipid species were also observed. Phosphatidylethanolamine levels were sharply reduced at 15 degrees C, in addition to a moderate increase in levels of unsaturated phospholipid fatty acids. Glycosphingolipids contained high levels of long-chain hydroxy fatty acids, which constituted 75% of the total fraction at 37 degrees C, but only 50% at 15 degrees C. Compositional changes were also observed in the long-chain base component of glycosphingolipids with respect to growth temperature. Fluorescence polarization studies indicate that the observed lipid modifications in 15 degrees C plasma membranes act to modulate bulk fluidity of the plasma-membrane lipids with respect to growth temperature. These studies suggest that coordinate modulation of glycosphingolipid, phospholipid and sterol content may be involved in regulation of plasma-membrane fluid properties during temperature acclimation.

Acclimatization↗
PubMed1994

Biosynthetic lipid-tagging of antibodies.

Chemical conjugation of fatty acids to antibodies generates lipid-modified molecules which have found use in the targeting of liposome-mediated drug delivery and in liposome-based immunoassays. Alternatively, bacterial expression of antibodies as single-chain FV fragments fused to lipoprotein signal peptide and N-terminal sequence leads to in vivo enzymatic addition of a single glycerolipid group at the N-terminus of the molecule. This lipid-modification converts the antibody from a soluble protein into a functional membrane-bound molecule. These biosynthetically lipid-tagged antibodies may prove useful for immobilization of antibodies to membranes in various biotechnological applications.

Antibodies↗
PubMed1998

Assessing the benefits of lipid-lowering therapy.

In recent years, a substantial body of evidence has emerged to support the use of lipid-lowering therapy in the prevention of coronary artery disease, and many physician groups have endorsed the management of dyslipidemia in at-risk patients. An important consideration in such endorsements has been the issue of the safety of lipid intervention; many early primary- and secondary-prevention studies reported either no reduction in all-cause mortality rates or an increase in non-coronary artery disease mortality rates in treated patients. These observations raised serious concerns about the safety of such therapy. However, 2 landmark studies, the Scandinavian Simvastatin Survival Study (4S) and the West of Scotland Coronary Prevention Study (WOSCOPS), have contributed greatly to alleviating these concerns. In this article, a review of the epidemiologic evidence supporting the use of lipid modification will be presented, including important trials and meta-analyses, and the cost-effectiveness of lipid-modifying treatment will be discussed.

Cause of Death↗
PubMed1999

Best practice--ongoing polemics.

Current treatment strategies and disease management programs for hyperlipidemia employ a range of lipid-lowering drugs. Results from early lipid-lowering trials using diet, fibrates, niacin and other classes of drug showed that lowering plasma cholesterol can significantly reduce the risk of developing ischemic cardiovascular events. The landmark statin trials have clearly demonstrated the benefits of lipid-lowering therapy in coronary heart disease (CHD) prevention and unlike early lipid-lowering studies, a reduction in mortality may become evident with statin therapy during the first year of treatment. The number of successful lipid-intervention trials continues to increase and evidence is accumulating that lipid modification can also reduce the risk of cardiovascular events among individuals with only modest degrees of blood-lipid abnormalities. With increasingly powerful drugs to modify blood lipids, the potential levels at which to initiate treatment and the appropriate target levels are rapidly changing and debate surrounds the question of where the line to initiate treatment should be drawn. The relative lack of major adverse events with statin therapy means that the level of CHD risk at which clinical benefit occurs cannot be determined by the degree of risk at which benefit exceeds adverse events. Therefore, patients with only moderately raised cholesterol levels can be treated because statin treatment is well tolerated. One of the most important aspects of the statin trials is the finding that clinical events, such as death and disability due to coronary artery disease, may be preventable or limited in a significant number of patients if they receive aggressive therapy. Current goals for cholesterol levels in patients with established CHD are rarely achieved with non-aggressive treatment; however, with aggressive lipid lowering statins can achieve these goals in a safe and effective manner.

Cardiovascular Diseases↗
PubMed1993

A novel N-terminal motif for palmitoylation of G-protein alpha subunits.

We have examined the post-translational processing of G alpha subunits expressed endogenously in rat PC12 and NG108-15 rat/mouse hybrid cells, and after transfection of cDNA expression constructs into COS cells. Thioester-linked palmitoylation of alpha o, alpha s, alpha q/alpha 11 and alpha 12 has been detected by metabolic labelling with [3H]palmitate and immunoprecipitation. Palmitoylation of alpha o occurs post-translationally in cells treated with protein-synthesis inhibitors, suggesting possible dynamic acylation. Palmitoylation of the C-terminal CAAX motif has been excluded. Site-directed mutagenesis of alpha o has been used to implicate the site of modification as a cysteine residue next to the N-terminal myristoylated glycine, in a novel protein-lipid modification motif Met-Gly-Cys. The non-palmitoylated alpha o mutant is still myristoylated but shows reduced membrane binding, suggesting that reversible palmitoylation may regulate G alpha localization and function.

Acylation↗
PubMed1999

An evidence-based assessment of the NCEP Adult Treatment Panel II guidelines. National Cholesterol Education Program.

CONTEXT: The Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) was issued without the benefit of multiple recently published large clinical trials. OBJECTIVE: To analyze the panel's guidelines for treatment of high cholesterol levels in the context of currently available clinical trial results. DATA SOURCES: MEDLINE was searched for all English-language clinical trial data from 1993 through February 1999 relating to the effects of cholesterol treatment on cardiovascular clinical outcomes. STUDY SELECTION: Studies that were selected for detailed review assessed the effects of cholesterol lowering on either coronary events, coronary mortality, stroke, and/or total mortality, preferably by randomized, double-blind, placebo-controlled design. Selection was by consensus of a general internist, a lipid clinic director, and a researcher in atherosclerotic plaque biology. A core of 37 of the 317 initially screened studies were selected and used as the primary means by which to assess the guidelines. DATA EXTRACTION: By consensus of the group, only prespecified end points of trials were included, unless post hoc analysis addressed issues not studied elsewhere. DATA SYNTHESIS: Recent clinical trial data mostly support the Adult Treatment Panel II guidelines for cholesterol management. While existing trials have validated the target low-density lipoprotein cholesterol (LDL-C) goals in the report, studies are lacking that address mortality benefit from reduction below these levels. Few lipid-lowering trials have treated patients with low high-density lipoprotein cholesterol and/or elevated triglyceride levels with LDL-C levels at or below treatment goals. CONCLUSIONS: Lipid-lowering therapy generally should be more aggressively applied to patients with diabetes and/or at the time of coronary heart disease (CHD) diagnosis. The evidence for statin use in secondary CHD prevention in postmenopausal women outweighs current evidence for use of estrogen replacement in this setting. Further studies are needed to address the effects of lipid modification in primary prevention of CHD in populations other than middle-aged men and to study markers of lipid metabolism other than LDL-C.

Adult↗
PubMed1995

Heterotetramer formation of prenylated Rab3A with two Rabphilin-3A molecules.

Rab3A small GTP-binding protein and its putative target protein, named Rabphilin-3A, are implicated in neurotransmitter release. We have investigated here the function of the lipid modifications of Rab3A (Mr approximately 25,000) in its interaction with Rabphilin-3A (Mr approximately 80,000). Lipid-modified GTP-Rab3A dimerized and lipid-unmodified one monomerized. Lipid-modified GTP-Rab3A (Mr approximately 50,000) formed a heterotetramer (Mr approximately 210,000) with two Rabphilin-3A molecules, whereas lipid-unmodified GTP-Rab3A formed a heterodimer (Mr approximately 105,000) with one Rabphilin-3A molecule. These results indicate that two lipid-modified GTP-Rab3A molecules form a heterotetramer with two Rabphilin-3A molecules.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Structural and functional crosstalk between acetylcholine receptor and its membrane environment.

Nicotinic acetylcholine receptor (AChR) is a transmembrane protein belonging to the superfamily of rapid, ligand-operated channels. Theoretical models based on thermodynamic criteria assign portions of the polypeptide chains to the lipid bilayer region. From an experimental point of view, however, the relationship between the two moieties remains largely unexplored. Current studies from our laboratory are aimed at defining the structural, dynamic, and functional relationship between membrane lipids and AChR. We are particularly interested in establishing the characteristics of and differences between the lipids in each leaflet of the bilayer and the belt or "annular" lipids immediately surrounding AChR and the bulk bilayer lipids. We are also interested in determining the possible implications of lipid modifications on AChR channel properties. Toward these ends, fluorescence and other spectroscopic techniques, together with biochemical analyses and patch-clamp studies, are currently being undertaken. Correlations can be established between structural aspects of phospholipid packing in the immediate perimeter of AChR and other properties of these annular lipids revealed by dynamic spectroscopic and molecular modeling techniques. Lipid compositional analyses of the clonal muscle cell line BC3H-1 and chemical modification studies have been carried out by incubation of intact cells in culture and of membrane patches excised therefrom with liposomes of different lipid composition. These studies have been combined with electrophysiological measurements using the patch-clamp technique, with the aim of determining the possible effects of lipids on the channel properties of muscle-type AChR. A variety of experimental conditions, involving polar head and fatty acyl chain substitution of phospholipids and cholesterol incorporation, are being assayed in the BC3H-1 cells.

Acetylcholine↗
PubMed2002

Sonic hedgehog in the nervous system: functions, modifications and mechanisms.

Signaling by Sonic hedgehog (Shh) controls important developmental processes, including dorsoventral neural tube patterning, neural stem cell proliferation, and neuronal and glial cell survival. Shh signaling involves lipid modifications to Shh itself, as well as changes in protein subcellular localization. Recent advances have revealed the importance of palmitoylation and acylation of Shh on its potency and migration capacity. Subsequent trafficking and organelle sorting in the Shh signaling pathway have been observed; these observations offer a new dimension to our understanding of downstream signal transduction events.

Animals↗
PubMed2005

Protein lipidation of BACE.

Our research has concentrated upon the protein lipid modification of BACE [beta-site amyloid precursor protein cleaving enzyme (beta-secretase)], of which very little is currently known. Lipidation influences the production of Abeta (amyloid beta-protein) by promoting the dimerization of BACE.

Alzheimer Disease↗
PubMed2004

What does the lipoprotein oxidation phenomenon mean?

The evidence that oxidative lipid modification may be involved in the genesis of common diseases, such as atherosclerosis, is persuasive, but it was, until recently, conjecture based on in vitro findings, or investigation using experimental animal models. Recent clinical intervention studies in patients at high risk of cardiovascular events have been, at best, inconclusive. This has led to a general consensus that antioxidant supplements are of no value in the prevention of cardiovascular disease in subjects at high risk. However, epidemiological studies have demonstrated that the protective effects of antioxidant supplements, specifically vitamin E, were particularly evident amongst healthy subjects taking supplements. The picture is further clouded by the uncertain mechanism of lipoprotein modification within the artery wall, the possibility that some antioxidants may, under certain conditions, become pro-oxidants, the complex interactions between lipid- and water-soluble antioxidants, and the fact that free-radical-mediated events may only be important in the early stages of atherogenesis. Recent results also suggest that the biological efficacy of antioxidants, such as alpha-tocopherol, may be compromised by the conditions extant within the plaque. It is evidently important that the position on the benefits of antioxidants, whether in food or as supplements, in disease prevention is clarified.

Animals↗
PubMed1983

Cold stress induces in situ phospholipid molecular species changes in cell surface membranes.

The structural organization of Tetrahymena pyriformis is such that its cilia are remote from the main centers of lipid metabolism. As a result, the ciliary membrane lipid composition of cells exposed to low-temperature stress is initially unaffected by the significant metabolic changes induced in microsomal membranes. Nevertheless, changes in the ciliary membrane lipid composition can be detected during the first 4 h of cold exposure. A combination of in vivo and in vitro experiments has provided strong evidence for a substantial retailoring of ciliary phospholipid molecular species in situ in the absence of any importation of lipids from the cell interior or change in overall ciliary fatty acid composition. The mechanism responsible for the ciliary lipid changes is independent of the one(s) triggering internal acclimation responses. Our observations establish for the first time that chilling stress can simultaneously induce separate and distinctive lipid modification responses in different parts of a cell. This finding could be important in identifying the molecular 'sensor' capable of actuating stress-induced lipid changes.

Acclimatization↗
PubMed2001

Hedgehog signaling: a tale of two lipids.

Hedgehog proteins constitute one of the major classes of intercellular signals that control inductive interactions during animal development. These proteins undergo unusual lipid modifications and signal through an unconventional transmembrane protein receptor that is characterized by a sequence motif implicated in sterol sensing. Recent studies suggest that the lipid adducts regulate the range and potency of the signals, whereas the sterol-sensing domain is essential for receptor activity.

Animals↗