Membrane-lipid therapy: a new approach in molecular medicine.

Although most drugs bind to proteins and regulate their activity, some drugs act through a new therapeutic approach called membrane-lipid therapy and bind to lipids, thus modulating the structure of membranes. Most cellular functions are highly dependent on the lipid environment because they are controlled by proteins in or around membranes. The wide variety of cell and organelle membranes and the existence of special lipid regions (e.g. microvilli) and domains (e.g. lipid rafts) support the possibility of designing specific lipid therapies. Indeed, recent evidence suggests that lipid therapy might have potential for the treatment of cancer, cardiovascular pathologies, neurodegenerative processes, obesity, metabolic disorders, inflammation, and infectious and autoimmune diseases.

[1]  T. Waldmann,et al.  Dynamic, yet structured: The cell membrane three decades after the Singer–Nicolson model , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Oh,et al.  Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default. , 2001, Molecular biology of the cell.

[3]  F. Goñi,et al.  Structure and functional properties of diacylglycerols in membranes. , 1999, Progress in lipid research.

[4]  P. Escribá,et al.  Disruption of cellular signaling pathways by daunomycin through destabilization of nonlamellar membrane structures. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Escribá,et al.  Membrane structure modulation, protein kinase C alpha activation, and anticancer activity of minerval. , 2005, Molecular pharmacology.

[6]  V. Picciarelli,et al.  Effect of Sterols on β-Amyloid Peptide (AβP 1–40) Channel Formation and their Properties in Planar Lipid Membranes , 2004 .

[7]  T. Saldeen,et al.  Fatty acid composition in total phospholipids of human coronary arteries in sudden cardiac death. , 1993, Atherosclerosis.

[8]  W. Stillwell,et al.  Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells , 2005, Breast Cancer Research.

[9]  Huey W. Huang,et al.  New phases of phospholipids and implications to the membrane fusion problem. , 2003, Biochemistry.

[10]  P. Escribá,et al.  The Gβγ Dimer Drives the Interaction of Heterotrimeric Gi Proteins with Nonlamellar Membrane Structures* , 2004, Journal of Biological Chemistry.

[11]  D. Mihăilescu,et al.  Interactions of some local anesthetics and alcohols with membranes. , 2001, Colloids and surfaces. B, Biointerfaces.

[12]  V. Ruíz-Gutiérrez,et al.  Triacylglycerol molecular species are depleted to different extents in the myocardium of spontaneously hypertensive rats fed two oleic acid-rich oils. , 2005, American journal of hypertension.

[13]  B S Polla,et al.  Curosurf modulates cAMP accumulation in human monocytes through a membrane-controlled mechanism. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[14]  P. Kinnunen On the molecular-level mechanisms of peripheral protein-membrane interactions induced by lipids forming inverted non-lamellar phases , 1996 .

[15]  V. Ruíz-Gutiérrez,et al.  The protective role of squalene in alcohol damage in the chick embryo retina. , 2005, Experimental eye research.

[16]  N. Chauhan,et al.  Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease Published, JLR Papers in Press, September 1, 2003. DOI 10.1194/jlr.R300010-JLR200 , 2003, Journal of Lipid Research.

[17]  G. Barceló-Coblijn,et al.  Modification by docosahexaenoic acid of age-induced alterations in gene expression and molecular composition of rat brain phospholipids , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  P. Kinnunen,et al.  Formation of amyloid fibers triggered by phosphatidylserine-containing membranes. , 2004, Biochemistry.

[19]  S. Collins,et al.  Beta-adrenergic receptors and regulation of energy expenditure: a family affair. , 2004, Annual review of pharmacology and toxicology.

[20]  R. Jacob,et al.  Membrane Microdomains and Vascular Biology: Emerging Role in Atherogenesis , 2003, Circulation.

[21]  J. González-Ros,et al.  Role of membrane lipids in the interaction of daunomycin with plasma membranes from tumor cells: implications in drug-resistance phenomena. , 1990, Biochemistry.

[22]  D. Quilliot,et al.  Erythrocyte membrane phospholipid composition is related to hyperinsulinemia in obese nondiabetic women: effects of weight loss. , 2002, Metabolism: clinical and experimental.

[23]  V. Ruíz-Gutiérrez,et al.  Plasma lipids, erythrocyte membrane lipids and blood pressure of hypertensive women after ingestion of dietary oleic acid from two different sources. , 1996, Journal of hypertension.

[24]  P. Escribá,et al.  Effects of oleic acid and its congeners, elaidic and stearic acids, on the structural properties of phosphatidylethanolamine membranes Published, JLR Papers in Press, December 16, 2002. DOI 10.1194/jlr.M200356-JLR200 , 2003, Journal of Lipid Research.

[25]  P. Escribá,et al.  2-Hydroxyoleic Acid: A New Hypotensive Molecule , 2004, Hypertension.

[26]  K Clark,et al.  The effect of age on the association between body-mass index and mortality. , 1998, Journal of insurance medicine.

[27]  M. St-Onge Dietary fats, teas, dairy, and nuts: potential functional foods for weight control? , 2005, The American journal of clinical nutrition.

[28]  S. Singer,et al.  The fluid mosaic model of the structure of cell membranes. , 1972, Science.

[29]  K. Sumino,et al.  Analysis of 7-ketocholesterol in low density lipoprotein and fatty acid composition in erythrocyte membranes of patients on maintenance hemodialysis and healthy controls. , 2000, Clinica chimica acta; international journal of clinical chemistry.

[30]  P. Csermely,et al.  Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  B. Lowell,et al.  βAR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance , 2002, Science.

[32]  S. Robins Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy? , 2003, Current opinion in lipidology.

[33]  T. Farkas,et al.  Search for the pathogenesis of the differing phenotype in two compound heterozygote Hungarian brothers with the same genotypic triosephosphate isomerase deficiency. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  W. Willett,et al.  Dietary fat, olive oil intake and breast cancer risk , 1994, International journal of cancer.

[35]  J. Killian,et al.  Tryptophan-anchored transmembrane peptides promote formation of nonlamellar phases in phosphatidylethanolamine model membranes in a mismatch-dependent manner. , 2000, Biochemistry.

[36]  J. Marrugat,et al.  Adherence to the traditional mediterranean diet is inversely associated with body mass index and obesity in a spanish population. , 2004, The Journal of nutrition.

[37]  D. Manning,et al.  Regulation of G proteins by covalent modification , 2001, Oncogene.

[38]  Sebastian Linser,et al.  Structural rearrangement of model membranes by the peptide antibiotic NK-2. , 2005, Biochimica et biophysica acta.

[39]  S. Singer,et al.  The Fluid Mosaic Model of the Structure of Cell Membranes , 1972, Science.

[40]  P. Escribá,et al.  Membrane phospholipid reorganization differentially regulates metallothionein and heme oxygenase by heme-hemopexin. , 2002, DNA and cell biology.

[41]  E. Gulbins,et al.  Rhinoviruses Infect Human Epithelial Cells via Ceramide-enriched Membrane Platforms* , 2005, Journal of Biological Chemistry.

[42]  Jeffrey K. Yao,et al.  Membrane phospholipids and cytokine interaction in schizophrenia. , 2004, International review of neurobiology.

[43]  P. Escribá,et al.  Role of lipid polymorphism in G protein-membrane interactions: nonlamellar-prone phospholipids and peripheral protein binding to membranes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. Escribá,et al.  Alteration of Lipids, G Proteins, and PKC in Cell Membranes of Elderly Hypertensives , 2003, Hypertension.

[45]  E. Dufourc,et al.  Cholesterol dynamics in membranes of raft composition: a molecular point of view from 2H and 31P solid-state NMR. , 2003, Biochemistry.

[46]  M. Farlow,et al.  Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M400486-JLR200 , 2005, Journal of Lipid Research.

[47]  G. Yee,et al.  The anticancer agent adriamycin can be actively cytotoxic without entering cells. , 1982, Science.

[48]  M. Perutz Protein Structure: New Approaches to Disease and Therapy , 1992 .

[49]  S. Sheikh,et al.  Synthesis and biological evaluation of gemcitabine-lipid conjugate (NEO6002). , 2005, Bioorganic & medicinal chemistry letters.

[50]  T. Shea Phospholipids alter tau conformation, phosphorylation, proteolysis, and association with microtubules: Implication for tau function under normal and degenerative conditions , 1997, Journal of neuroscience research.

[51]  A. Simopoulos Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases , 2002, Journal of the American College of Nutrition.

[52]  P. Comfurius,et al.  Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. , 2004, Biochimica et biophysica acta.

[53]  N. Arispe,et al.  Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AβP (1–40) and (1–42) peptides , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[54]  Philip Yeagle,et al.  The Structure of Biological Membranes , 2004 .

[55]  X. Busquets,et al.  Differential modulation of protein kinase C isoforms in erythroleukemia during induced differentiation. , 1993, Cancer research.

[56]  D. Zakim,et al.  Membrane fluidity and the regulation of membrane-bound enzymes. , 1974, Horizons in biochemistry and biophysics.

[57]  R. Epand,et al.  CTP:phosphocholine cytidylyltransferase and protein kinase C recognize different physical features of membranes: differential responses to an oxidized phosphatidylcholine. , 2002, Biochimica et biophysica acta.

[58]  G. Barceló-Coblijn,et al.  Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Watt W. Webb,et al.  Imaging coexisting fluid domains in biomembrane models coupling curvature and line tension , 2003, Nature.

[60]  L. Tecott,et al.  Up-Regulation of Peroxisome Proliferator-Activated Receptors (PPAR-α) and PPAR-γ Messenger Ribonucleic Acid Expression in the Liver in Murine Obesity: Troglitazone Induces Expression of PPAR-γ-Responsive Adipose Tissue-Specific Genes in the Liver of Obese Diabetic Mice* * This work was supported by , 2000, Endocrinology.

[61]  L. Tecott,et al.  Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. , 2000, Endocrinology.

[62]  T. Crook,et al.  Effects of phosphatidylserine in Alzheimer's disease. , 1992, Psychopharmacology bulletin.

[63]  P. Escribá,et al.  The hypotensive drug 2-hydroxyoleic acid modifies the structural properties of model membranes , 2004, Molecular membrane biology.

[64]  P. Parker The ubiquitous phosphoinositides. , 2004, Biochemical Society transactions.

[65]  Anthony G Lee,et al.  How lipids affect the activities of integral membrane proteins. , 2004, Biochimica et biophysica acta.

[66]  John P. Overington,et al.  Prioritizing the proteome: identifying pharmaceutically relevant targets. , 2002, Drug discovery today.

[67]  R. Handrick,et al.  Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitisers. , 2003, Current medicinal chemistry. Anti-cancer agents.

[68]  Michael J. González,et al.  Erythrocyte membrane fatty acid composition in cancer patients. , 2004, Puerto Rico health sciences journal.

[69]  P. Escribá,et al.  Influence of the Membrane Lipid Structure on Signal Processing via G Protein-Coupled Receptors , 2005, Molecular Pharmacology.

[70]  P. Escribá,et al.  Effects of unsaturated fatty acids and triacylglycerols on phosphatidylethanolamine membrane structure Published, JLR Papers in Press, June 16, 2003. DOI 10.1194/jlr.M300092-JLR200 , 2003, Journal of Lipid Research.

[71]  Giuseppe Miserocchi,et al.  Compositional changes in lipid microdomains of air-blood barrier plasma membranes in pulmonary interstitial edema. , 2003, Journal of applied physiology.

[72]  R. Epand,et al.  Role of phospholipids containing docosahexaenoyl chains in modulating the activity of protein kinase C. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[73]  P. Escribá,et al.  Farnesol and geranylgeraniol modulate the structural properties of phosphatidylethanolamine model membranes , 2005, Molecular membrane biology.

[74]  A. Hendrich,et al.  Lipids as a target for drugs modulating multidrug resistance of cancer cells. , 2003, Current drug targets.

[75]  Lan Ma,et al.  Agonist-induced Formation of Opioid Receptor-G Protein-coupled Receptor Kinase (GRK)-Gβγ Complex on Membrane Is Required for GRK2 Function in Vivo* , 2003, Journal of Biological Chemistry.

[76]  Lucarelli,et al.  Physicochemical and functional modifications induced by obesity on human erythrocyte membranes , 1999, European journal of clinical investigation.

[77]  S. Marčelja,et al.  Physical principles of membrane organization , 1980, Quarterly Reviews of Biophysics.