The Homeodomain Derived Peptide Penetratin Induces Curvature of Fluid Membrane Domains

BACKGROUND:Protein membrane transduction domains that are able to cross the plasma membrane are present in several transcription factors, such as the homeodomain proteins and the viral proteins such as Tat of HIV-1. Their discovery resulted in both new concepts on the cell communication during development, and the conception of cell penetrating peptide vectors for internalisation of active molecules into cells. A promising cell penetrating peptide is Penetratin, which crosses the cell membranes by a receptor and metabolic energy-independent mechanism. Recent works have claimed that Penetratin and similar peptides are internalized by endocytosis, but other endocytosis-independent mechanisms have been proposed. Endosomes or plasma membranes crossing mechanisms are not well understood. Previously, we have shown that basic peptides induce membrane invaginations suggesting a new mechanism for uptake, "physical endocytosis". METHODOLOGY/PRINCIPAL FINDINGS:Herein, we investigate the role of membrane lipid phases on Penetratin induced membrane deformations (liquid ordered such as in "raft" microdomains versus disordered fluid "non-raft" domains) in membrane models. Experimental data show that zwitterionic lipid headgroups take part in the interaction with Penetratin suggesting that the external leaflet lipids of cells plasma membrane are competent for peptide interaction in the absence of net negative charges. NMR and X-ray diffraction data show that the membrane perturbations (tubulation and vesiculation) are associated with an increase in membrane negative curvature. These effects on curvature were observed in the liquid disordered but not in the liquid ordered (raft-like) membrane domains. CONCLUSIONS/SIGNIFICANCE:The better understanding of the internalisation mechanisms of protein transduction domains will help both the understanding of the mechanisms of cell communication and the development of potential therapeutic molecular vectors. Here we showed that the membrane targets for these molecules are preferentially the fluid membrane domains and that the mechanism involves the induction of membrane negative curvature. Consequences on cellular uptake are discussed

La lipidomique comme outil de théranostic

PARIS-BIUP (751062107) / SudocSudocFranceF

Perturbations of Lipid Metabolism Indexed by Lipidomic Biomarkers

The lipidome of the liver and the secreted circulating lipoproteins can now be interrogated conveniently by automated mass spectrometric methods. Multivariate analysis of the liver and serum lipid composition in various animal modes or in human patients has pointed to specific molecular species markers. The perturbations of lipid metabolism can be categorized on the basis of three basic pathological mechanisms: (1) an accelerated rate of de novo lipogenesis; (2) perturbation of the peroxisome pathway of ether-lipid and very-long-chain fatty acid biosynthesis; (3) a change in the rate of interconversion of essential omega-3 and -6 polyunsaturated fatty acids. This review provides examples to illustrate the practicalities of lipidomic studies in biomedicine

Application of Lipidomics to Assess Lipogenesis in Drug Development and Pre-Clinical Trials

International audienceThe rising incidence of cardiovascular and metabolic diseases in industrialized countries has led the pharmaceutical industry to make them key areas of drug development. These diseases imply a clustering of metabolic factors where lipid metabolites play a relevant role. Measurement of pharmacodynamic endpoints of drugs on lipid metabolism pathways and downstream biological processes appear crucial for a rational drug discovery/development. Fortunately, recent mass spectrometers with an enhanced sensitivity and resolution in combination with multivariate statistical analysis provide the practical possibility to analyze and measure wide portions of the lipidome. The final goal is to identify lipid signatures which fit with specific pharmacologic responses to therapeutic intervention. Focusing on applications of lipidomics for drug development this review outlines the methodological steps, from analytical measurements to data processing and to graphical representation, for an efficient implementation of informative lipid signatures

HDLs induce raft domain vanishing in heterogeneous giant vesicles

International audienceCholesterol efflux from the plasma membrane to HDLs is essential for cell cholesterol homeostasis. Recently, cholesterol-enriched ordered membrane domains, i.e. lipid rafts have been proposed to play an important role in this process. Here we introduce a new method to investigate the role of HDL interactions with the raft lipid phase and to directly visualize the effects of HDL-induced cholesterol efflux on rafts in model membranes. Addition of HDLs to giant lipid vesicles containing raft-type domains promoted decrease in size and disappearance of such domains as visualized by fluorescence microscopy. This was interpreted as resulting from cholesterol efflux from the vesicles to the HDLs. The raft vanishing rate was directly related to the HDL concentration. Evidence for a direct interaction of HDLs with the membrane was obtained by observing mutual adhesion of vesicles. It is suggested that the present method can be used to study the selective role of the bilayer lipid phase (raft and non-raft) in cholesterol efflux and membrane–HDL interaction and their underlying mechanisms. Such mechanisms may contribute to cholesterol efflux in vivo

Diurnal Interplay between Epithelium Physiology and Gut Microbiota as a Metronome for Orchestrating Immune and Metabolic Homeostasis

The behavior and physiology of most organisms are temporally coordinated and aligned with geophysical time by a complex interplay between the master and peripheral clocks. Disruption of such rhythmic physiological activities that are hierarchically organized has been linked to a greater risk of developing diseases ranging from cancer to metabolic syndrome. Herein, we summarize the molecular clockwork that is employed by intestinal epithelial cells to anticipate environmental changes such as rhythmic food intake and potentially dangerous environmental stress. We also discuss recent discoveries contributing to our understanding of how a proper rhythm of intestinal stem cells may achieve coherence for the maintenance of tissue integrity. Emerging evidence indicates that the circadian oscillations in the composition of the microbiota may operate as an important metronome for the proper preservation of intestinal physiology and more. Furthermore, in this review, we outline how epigenetic clocks that are based on DNA methylation levels may extensively rewire the clock-controlled functions of the intestinal epithelium that are believed to become arrhythmic during aging

Lipides membranaires dans la schizophrénie et la psychose débutante : de potentiels biomarqueurs et pistes thérapeutiques ?

International audienceThe various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.Les lipides membranaires jouent un rôle important dans le fonctionnement cérébral et peuvent désormais être étudiés de manière précise. Cette revue vise à familiariser le lecteur avec les lipides membranaires et les conséquences de leurs anomalies dans les troubles du spectre schizophrénique. Nous nous intéresserons aux données concernant les acides gras poly-insaturés (AGPI), les phospholipides et les sphingolipides membranaires, dans la schizophrénie, notamment dans ses phases débutantes et dans les modèles animaux correspondants. Chez l’animal, une carence en oméga-3 entraîne des anomalies neuro-développementales, tandis qu’une supplémentation en oméga-3 a un effet protecteur dans certains modèles. Chez l’homme, une altération dans la concentration membranaire en oméga-3 est observée chez certains patients. Le déficit en AGPI a été décrit comme associé à des anomalies de myélinisation et des troubles cognitifs. Des anomalies similaires peuvent également être retrouvées chez certains sujets lors du premier épisode psychotique (PEP) ou à ultra-haut risque (UHR) et certaines études suggèrent un effet bénéfique d’une supplémentation en oméga-3. Ainsi, l’identification d’une anomalie de la composition des lipides membranaires pourrait servir de biomarqueur chez certains patients, qui pourraient bénéficier d’une supplémentation en oméga-3. Dans ce contexte, l’étude de la composition des anomalies lipidiques membranaires pourrait permettre de prédire la transition psychotique ou le pronostic fonctionnel et cognitif et d’optimiser leur prise en charge. De nouvelles études sur les lipides membranaires sont nécessaires pour mieux comprendre leur implication en psychiatrie et se diriger vers une médecine personnalisée

SPHINGOMYELIN DECREASE IN RBC MEMBRANE OF SCHIZOPHRENIA PATIENTS IS ASSOCIATED WITH A PATTERN OF OTHER MEMBRANE LIPID ABNORMALITIES AND DISEASE SEVERITY

status: publishe

CYP46A1 protects against NMDA-mediated excitotoxicity in Huntington's disease: Analysis of lipid raft content

International audienc