Determinants of cholesterol efflux capacity in humans Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-12-18 Charlotte P.J. Talbot, Jogchum Plat, Andreas Ritsch, Ronald P. Mensink
High-density lipoproteins (HDL) play an important role in the reverse cholesterol transport (RCT) pathway, contributing to the efflux of excess cellular cholesterol. However, the classic hypothesis that raising HDL-cholesterol (HDL-C) concentrations reduces cardiovascular disease (CVD) risk has been challenged by recent intervention studies. Nowadays, improving cholesterol efflux capacity of HDL particles is considered to be a better target for the prevention of CVD. We will first briefly summarize assays that have been developed in order to quantify HDL-mediated cholesterol efflux from macrophages. However, the main purpose of this review is to discuss factors and ABC-transporters that are associated with HDL-mediated cholesterol efflux, such as HDL particle characteristics (i.e. HDL size and composition), subjects' characteristics (i.e. gender, BMI and age), HDL-C raising drugs, lifestyle, genetic background, as well as acute and low-grade systemic inflammation. Results suggested that factors associated with small HDL particles efficiently promote cholesterol efflux via the ABCA1 transporter. This appears to contradict findings from epidemiological studies suggesting that in particular large HDL2 particles are related to a reduced CVD risk. It is therefore essential not only to understand targets to increase cholesterol efflux capacity, but also to prove causality between cholesterol efflux capacity and the prevention of CVD risk.
Exploring the functional significance of sterol glycosyltransferase enzymes Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-11-21 Gaurav Singh, Yogeshwar Vikram Dhar, Mehar Hasan Asif, Pratibha Misra
Steroidal alkaloids (SAs) are widely synthesized and distributed in plants manifesting as natural produce endowed with potential for medicinal, pesticidal and other high-value usages. Glycosylation of these SAs raises complex and diverse glycosides in plant cells that indeed govern numerous functional aspects. During the glycosylation process of these valuable metabolites, the addition of carbohydrate molecule(s) is catalyzed by enzymes known as sterol glycosyltransferases (SGTs), commonly referred to as UGTs, leading to the production of steryl glycosides (SGs). The ratio of SGs and nonglyco-conjugated SAs are different in different plant species, however, their biosynthesis in the cell is controlled by different environmental factors. The aim of this review is to evaluate the current SGT enzyme research and the functional consequences of glycomodification of SAs on the physiology and plant development, which together are associated with the plant's primary processes. Pharmaceutical, industrial, and other potential uses of saponins have also been discussed and their use in therapeutics has been unveiled by in silico analysis. The field of biotransformation or conversion of nonglycosylated to glycosylated phytosterols by the activity of SGTs, making them soluble, available and more useful for humankind is the new field of interest towards drug therapy.
Furan fatty acids – Beneficial or harmful to health? Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-10-16 Long Xu, Andrew J. Sinclair, Muniba Faiza, Daoming Li, Xianlin Han, Huiyong Yin, Yonghua Wang
Furan fatty acids are found in plants, algae, and fish, and reported to have some positive health benefits, including anti-oxidant and anti-inflammatory activities, and inhibition of non-enzymatic lipid peroxidation. A major metabolite of furan fatty acids, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), has been reported to be increased in patients who progress from prediabetes to type 2 diabetes, although CMPF is not necessarily associated with impaired glucose metabolism. Other studies report that CMPF levels are lower in subjects with diabetes than control subjects. Plasma CMPF levels increase in subjects who consume fish or fish oil, and in patients with renal failure. It is not known where furan fatty acids are converted to CMPF and it is speculated that this might be a result of microbiome activity. The plasma levels reported for CMPF in healthy, diabetic and patients with renal disease vary by factors of more than 100-fold within each of these three groups, so measurement error appears to be limiting the ability to interpret studies. This review explores these controversies and raises questions about whether CMPF is a marker for healthy diets or indeed associated with diabetes and renal health. The review concludes that, on balance, furan fatty acids are beneficial for health.
Modulating fat digestion through food structure design Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-10-07 Qing Guo, Aiqian Ye, Nick Bellissimo, Harjinder Singh, Dérick Rousseau
Dietary fats and oils are an important component of our diet and a significant contributor to total energy and intake of lipophilic nutrients and bioactives. We discuss their fate in a wide variety of engineered, processed and naturally-occurring foods as they pass through the gastrointestinal tract and the implicit role of the food matrix within which they reside. Important factors that control fat and oil digestion include: 1) Their physical state (liquid or solid); 2) Dispersion of oil as emulsion droplets and control of the interfacial structure of emulsified oils; 3) The structure and rheology of the food matrix surrounding dispersed oil droplets; and 4) Alteration of emulsified oil droplet size and concentration. Using examples based on model foods such as emulsion gels and everyday foods such as almonds and cheese, we demonstrate that food structure design may be used as a tool to modulate fat and oil digestion potentially resulting in a number of targeted physiological outcomes.
Isoprostanes, neuroprostanes and phytoprostanes. An overview of 25 years of research in chemistry and biology Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-09-18 Jean-Marie Galano, Yiu Yiu Lee, Camille Oger, Claire Vigor, Joseph Vercauteren, Thierry Durand, Martin Giera, Jetty Chung-Yung Lee
Since the beginning of the 1990's diverse types of metabolites originating from polyunsaturated fatty acids, formed under autooxidative conditions were discovered. Known as prostaglandin isomers (or isoprostanoids) originating from arachidonic acid, neuroprostanes from docosahexaenoic acid, and phytoprostanes from α-linolenic acid proved to be prevalent in biology. The syntheses of these compounds by organic chemists and the development of sophisticated mass spectrometry methods has boosted our understanding of the isoprostanoid biology. In recent years, it has become accepted that these molecules not only serve as markers of oxidative damage but also exhibit a wide range of bioactivities. In addition, isoprostanoids have emerged as indicators of oxidative stress in humans and their environment. This review explores in detail the isoprostanoid chemistry and biology that has been achieved in the past three decades.
Applications of nuclear magnetic resonance in lipid analyses: An emerging powerful tool for lipidomics studies Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-09-11 Jingbo Li, Thomas Vosegaard, Zheng Guo
The role of lipids in cell, tissue, and organ physiology is crucial; as many diseases, including cancer, diabetes, neurodegenerative, and infectious diseases, are closely related to absorption and metabolism of lipids. Mass spectrometry (MS) based methods are the most developed powerful tools to study the synthetic pathways and metabolic networks of cellular lipids in biological systems; leading to the birth of an emerging subject lipidomics, which has been extensively reviewed. Nuclear magnetic resonance (NMR), another powerful analytical tool, which allows the visualization of single atoms and molecules, is receiving increasing attention in lipidomics analyses. However, very little work focusing on lipidomic studies using NMR has been critically reviewed. This paper presents a first comprehensive summary of application of 1H, 13C & 31P NMR in lipids and lipidomics analyses. The scientific basis, principles and characteristic diagnostic peaks assigned to specific atoms/molecular structures of lipids are presented. Applications of 2D NMR in mapping and monitoring of the components and their changes in complex lipids systems, as well as alteration of lipid profiling over disease development are also reviewed. The applications of NMR lipidomics in diseases diagnosis and food adulteration are exemplified.
Bacterial conjugated linoleic acid production and their applications Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-09-07 Bo Yang, He Gao, Catherine Stanton, R. Paul Ross, Hao Zhang, Yong Q. Chen, Haiqin Chen, Wei Chen
Conjugated linoleic acid (CLA) has been shown to exert various potential physiological properties including anti-carcinogenic, anti-obesity, anti-cardiovascular and anti-diabetic activities, and consequently has been considered as a promising food supplement. Bacterial biosynthesis of CLA is an attractive approach for commercial production due to its high isomer-selectivity and convenient purification process. Many bacterial species have been reported to convert free linoleic acid (LA) to CLA, hitherto only the precise CLA-producing mechanisms in Propionibacterium acnes and Lactobacillus plantarum have been illustrated completely, prompting the development of recombinant technology used in CLA production. The purpose of the article is to review the bacterial CLA producers as well as the recent progress on describing the mechanism of microbial CLA-production. Furthermore, the advances and potential in the heterologous expression of CLA genetic determinants will be presented.
The renaissance of lipoprotein(a): Brave new world for preventive cardiology? Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-09-06 Katrina L. Ellis, Michael B. Boffa, Amirhossein Sahebkar, Marlys L. Koschinsky, Gerald F. Watts
Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine.“Progress lies not in enhancing what is, but in advancing toward what will be.” (Khalil Gibran)
Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-08-01 M.C. Teixeira, C. Carbone, E.B. Souto
Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided.
Implications of glycerol metabolism for lipid production Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-08-01 Lu-Lu Xue, Hao-Hong Chen, Jian-Guo Jiang
Triacylglycerol (TAG) is an important product in oil-producing organisms. Biosynthesis of TAG can be completed through either esterification of fatty acids to glycerol backbone, or through esterification of 2-monoacylglycerol. This review will focus on the former pathway in which two precursors, fatty acid and glycerol-3-phosphate (G3P), are required for TAG formation. Tremendous progress has been made about the enzymes or genes that regulate the biosynthetic pathway of TAG. However, much attention has been paid to the fatty acid provision and the esterification process, while the possible role of G3P is largely neglected. Glycerol is extensively studied on its usage as carbon source for value-added products, but the modification of glycerol metabolism, which is directly associated with G3P synthesis, is seldom recognized in lipid investigations. The relevance among glycerol metabolism, G3P synthesis and lipid production is described, and the role of G3P in glycerol metabolism and lipid production are discussed in detail with an emphasis on how G3P affects lipid production through the modulation of glycerol metabolism. Observations of lipid metabolic changes due to glycerol related disruption in mammals, plants, and microorganisms are introduced. Altering glycerol metabolism results in the changes of final lipid content. Possible regulatory mechanisms concerning the relationship between glycerol metabolism and lipid production are summarized.
Oleic acid-derived oleoylethanolamide: A nutritional science perspective Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-04-05 Kate J. Bowen, Penny M. Kris-Etherton, Gregory C. Shearer, Sheila G. West, Lavanya Reddivari, Peter J.H. Jones
The fatty acid ethanolamide oleoylethanolamide (OEA) is an endogenous lipid mediator derived from the monounsaturated fatty acid, oleic acid. OEA is synthesized from membrane glycerophospholipids and is a high-affinity agonist of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPAR-α). Dietary intake of oleic acid elevates circulating levels of OEA in humans by increasing substrate availability for OEA biosynthesis. Numerous clinical studies demonstrate a beneficial relationship between high-oleic acid diets and body composition, with emerging evidence to suggest OEA may mediate this response through modulation of lipid metabolism and energy intake. OEA exposure has been shown to stimulate fatty acid uptake, lipolysis, and β-oxidation, and also promote food intake control. Future research on high-oleic acid diets and body composition is warranted to confirm these outcomes and elucidate the underlying mechanisms by which oleic acid exerts its biological effects. These findings have significant practical implications, as the oleic acid-derived OEA molecule may be a promising therapeutic agent for weight management and obesity treatment.
HDL abnormalities in familial hypercholesterolemia: Focus on biological functions Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-05-12 Shiva Ganjali, Amir Abbas Momtazi, Maciej Banach, Petri T. Kovanen, Evan A. Stein, Amirhossein Sahebkar
Although a selective strong elevation in the plasma level of low-density lipoprotein (LDL) cholesterol is the hallmark of familial hypercholesterolemia (FH), also other plasma lipoprotein and lipid subspecies are changed in these patients. Several studies in FH patients have pointed to the qualitative abnormalities of high-density lipoprotein (HDL) particles, including their triglyceride and sphingomyelin enrichment, reduced capacity to promote cholesterol efflux from macrophages, impaired anti-inflammatory and anti-oxidant activities, and reduced plasma levels of miRs regulating HDL-dependent cholesterol efflux from macrophage foam cells, typical of atherosclerotic lesions. Thus, accurate understanding of HDL functionality and its disturbances in FH may serve a better estimation of the prognosis and also provide additional clues when searching for novel therapeutic choices in this disease. In spite of such a potential promise, there has been no prior comprehensive review focusing on indices of HDL function in FH patients. In the present review, we aim to fulfill this gap by identifying measures of HDL function that are impaired in FH, and by providing a concise summary on the impact of different lipid-modifying therapies on HDL functionality in FH.
Emerging roles for conjugated sterols in plants Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-06-27 Albert Ferrer, Teresa Altabella, Montserrat Arró, Albert Boronat
In plants, sterols are found in free form (free sterols, FSs) and conjugated as steryl esters (SEs), steryl glycosides (SGs) and acyl steryl glycosides (ASGs). Conjugated sterols are ubiquitously found in plants but their relative contents highly differ among species and their profile may change in response to developmental and environmental cues. SEs play a central role in membrane sterol homeostasis and also represent a storage pool of sterols in particular plant tissues. SGs and ASGs are main components of the plant plasma membrane (PM) that specifically accumulate in lipid rafts, PM microdomains known to mediate many relevant cellular processes. There are increasing evidences supporting the involvement of conjugated sterols in plant stress responses. In spite of this, very little is known about their metabolism. At present, only a limited number of genes encoding enzymes participating in conjugated sterol metabolism have been cloned and characterized in plants. The aim of this review is to update the current knowledge about the tissue and cellular distribution of conjugated sterols in plants and the enzymes involved in their biosynthesis. We also discuss novel aspects on the role of conjugated sterols in plant development and stress responses recently unveiled using forward- and reverse-genetic approaches.
Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals ☆ Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-06-09 Daniel W. Nebert
The basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family comprises many transcription factors, found throughout all three kingdoms of life; bHLH/PAS members “sense” innumerable intracellular and extracellular “signals” — including endogenous compounds, foreign chemicals, gas molecules, redox potential, photons (light), gravity, heat, and osmotic pressure. These signals then initiate downstream signaling pathways involved in responding to that signal. The term “PAS”, abbreviation for “per-Arnt-sim” was first coined in 1991. Although the mouse Arnt gene was not identified until 1991, evidence of its co-transcriptional binding partner, aryl hydrocarbon receptor (AHR), was first reported in 1974 as a “sensor” of foreign chemicals, up-regulating cytochrome P450 family 1 (CYP1) and other enzyme activities that usually metabolize the signaling chemical. Within a few years, AHR was proposed also to participate in inflammation. The mouse [Ah] locus was shown (1973–1989) to be relevant to chemical carcinogenesis, mutagenesis, toxicity and teratogenesis, the mouse Ahr gene was cloned in 1992, and the first Ahr(−/−) knockout mouse line was reported in 1995. After thousands of studies from the early 1970s to present day, we now realize that AHR participates in dozens of signaling pathways involved in critical-life processes, affecting virtually every organ and cell-type in the animal, including many invertebrates.
Polyunsaturated fatty acids and recurrent mood disorders: Phenomenology, mechanisms, and clinical application Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-01-06 Erik Messamore, Daniel M. Almeida, Ronald J. Jandacek, Robert K. McNamara
A body of evidence has implicated dietary deficiency in omega-3 polyunsaturated fatty acids (n-3 PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology and etiology of recurrent mood disorders including major depressive disorder (MDD) and bipolar disorder. Cross-national and cross-sectional evidence suggests that greater habitual intake of n-3 PUFA is associated with reduced risk for developing mood symptoms. Meta-analyses provide strong evidence that patients with mood disorders exhibit low blood n-3 PUFA levels which are associated with increased risk for the initial development of mood symptoms in response to inflammation. While the etiology of this n-3 PUFA deficit may be multifactorial, n-3 PUFA supplementation is sufficient to correct this deficit and may also have antidepressant effects. Rodent studies suggest that n-3 PUFA deficiency during perinatal development can recapitulate key neuropathological, neurochemical, and behavioral features associated with mood disorders. Clinical neuroimaging studies suggest that low n-3 PUFA biostatus is associated with abnormalities in cortical structure and function also observed in mood disorders. Collectively, these findings implicate dietary n-3 PUFA insufficiency, particularly during development, in the pathophysiology of mood dysregulation, and support implementation of routine screening for and treatment of n-3 PUFA deficiency in patients with mood disorders.
Sphingolipids and glycerophospholipids – The “ying and yang” of lipotoxicity in metabolic diseases Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-01-16 S. Rodriguez-Cuenca, V. Pellegrinelli, M. Campbell, M. Oresic, A. Vidal-Puig
Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of “ying/yang” interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.
Lipids in exosomes: Current knowledge and the way forward Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-03-23 Tore Skotland, Kirsten Sandvig, Alicia Llorente
Lipids are essential components of exosomal membranes, and it is well-known that specific lipids are enriched in exosomes compared to their parent cells. In this review we discuss current knowledge about the lipid composition of exosomes. We compare published data for different lipid classes in exosomes, and what is known about their lipid species, i.e. lipid molecules with different fatty acyl groups. Moreover, we elaborate on the hypothesis about hand-shaking between the very-long-chain sphingolipids in the outer leaflet and PS 18:0/18:1 in the inner leaflet, and we propose this to be an important mechanism in membrane biology, not only for exosomes. The similarity between the lipid composition of exosomes, HIV particles, and detergent resistant membranes, used as lipid rafts models, is also discussed. Furthermore, we summarize knowledge about the role of specific lipids and lipid metabolizing enzymes on the formation and release of exosomes. Finally, the use of exosomal lipids as biomarkers and how the lipid composition of exosomes may be of importance for researchers aiming to use exosomes as drug delivery vehicles is discussed. In conclusion, we have summarized what is presently known about lipids in exosomes and identified issues that should be taken into consideration in future studies.
A global perspective on FOXO1 in lipid metabolism and lipid-related diseases Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-04-06 Yue Li, Zhiqiang Ma, Shuai Jiang, Wei Hu, Tian Li, Shouyin Di, Dongjin Wang, Yang Yang
Lipid metabolism is a complex physiological process that is involved in nutrient adjustment, hormone regulation, and homeostasis. An unhealthy lifestyle and chronic nutrient overload can cause lipid metabolism disorders, which may lead to serious lipid-related diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus (T2DM). Therefore, tools for preventing dysfunctional lipid metabolism are urgently needed. The transcription factor forkhead box protein O1 (FOXO1) is involved in lipid metabolism and plays a critical role in the development of lipid-related diseases. In this review, we provide a global perspective on the role of FOXO1 in lipid metabolism and lipid-related diseases. The information included here may be useful for the design of future studies and advancing investigations of FOXO1 as a therapeutic target.
Prostaglandin synthases: Molecular characterization and involvement in prostaglandin biosynthesis Prog. Lipid. Res. (IF 10.583) Pub Date : 2017-04-07 Min-Ju Seo, Deok-Kun Oh
Prostaglandins (PGs) belong to a subclass of eicosanoids and are classified based on the structures of the cyclopentane ring and their number of double bonds in their hydrocarbon structures. PGs are important lipid mediators that are involved in inflammatory response. The biosynthesis of diverse PGs from unsaturated C20 fatty acids containing at least three double bonds such as dihomo-γ-linoleic acid (20:3Δ8Z,11Z,14Z), arachidonic acid (20:4Δ5Z,8Z,11Z,14Z), and eicosapentaenoic acid (20:5Δ5Z,8Z,11Z,14Z,17Z) is enables by various PG synthases, including prostaglandin H synthase (PGHS), 15-hydroxyprostaglandin dehydrogenase (15-HPGD), PGES, PGDS, PGFS, PGIS, and thromboxane A synthase (TXAS). This review summarizes the biochemical properties, reaction mechanism, and active site details of PG synthases. Because PGs are involved in the immune system, an understanding of PG synthases is important in the design of new anti-inflammatory drugs. The biosynthesis of PGs in various organisms, such as mammals, corals, florideae (a class of red algae), yeast, and fungi, is also introduced. The expression of PG synthases in the microbial systems for the synthesis of PGs is discussed. Now, the biosynthesis of PGs from glucose or glycerol is possible using metabolically engineered cells expressing both unsaturated fatty acid-producing enzymes and PG synthases.
Best practices for design and implementation of human clinical trials studying dietary oils Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-10-26 Dylan S. Mackay, Stephanie Jew, Peter J.H. Jones
Dietary oils are a significant contributor to overall energy and fatty acid intakes. Changes in the amount and/or type of dietary oils consumed have the potential to impact human health. Clinical trials represent the gold standard for testing the health impacts of such changes in dietary oils. The objective of this review is to explore best practices for clinical trials examining impacts of dietary oils including 1) pre-clinical topics such as research question generation, study design, participant population, outcome measures and intervention product selection and/or preparation; 2) clinical trial implementation topics such as recruitment, trial management, record keeping and compliance monitoring; and 3) post-clinical trial topics dealing with sample analysis and storage as well as management, publication and data access. The use of digital case report forms, and the best practices in reporting and publishing results are also addressed. In summary, properly designed and implemented clinical trials studying dietary oils produce strong scientific evidence-guiding their use.
Importance of phosphatidylcholine on the chloroplast surface Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-11-19 César Botella, Juliette Jouhet, Maryse A Block
In plant cells, phosphatidylcholine (PC) is a major glycerolipid of most membranes but practically lacking from the plastid internal membranes. In chloroplasts, PC is absent from the thylakoids and the inner envelope membrane. It is however the main component of the outer envelope membrane, where it exclusively distributes in the outer monolayer. This unique distribution is likely related with operational compartmentalization of plant lipid metabolism. In this review, we summarize the different mechanisms involved in homeostasis of PC in plant cells. The specific origin of chloroplast PC is examined and the involvement of the P4-ATPase family of phospholipid flippases (ALA) is considered with a special attention to the recently reported effect of the endoplasmic reticulum-localized ALA10 on modification of chloroplast PC desaturation. The different possible roles of chloroplast PC are then discussed and analyzed in consideration of plant physiology.
Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-12-08 Daniela Lopes, Sven Jakobtorweihen, Cláudia Nunes, Bruno Sarmento, Salette Reis
Lipid membranes work as barriers, which leads to inevitable drug-membrane interactions in vivo. These interactions affect the pharmacokinetic properties of drugs, such as their diffusion, transport, distribution, and accumulation inside the membrane. Furthermore, these interactions also affect their pharmacodynamic properties with respect to both therapeutic and toxic effects. Experimental membrane models have been used to perform in vitro assessment of the effects of drugs on the biophysical properties of membranes by employing different experimental techniques. In in silico studies, molecular dynamics simulations have been used to provide new insights at an atomistic level, which enables the study of properties that are difficult or even impossible to measure experimentally. Each model and technique has its advantages and disadvantages. Hence, combining different models and techniques is necessary for a more reliable study. In this review, the theoretical backgrounds of these (in vitro and in silico) approaches are presented, followed by a discussion of the pharmacokinetic and pharmacodynamic properties of drugs that are related to their interactions with membranes. All approaches are discussed in parallel to present for a better connection between experimental and simulation studies. Finally, an overview of the molecular dynamics simulation studies used for drug-membrane interactions is provided.
Phospholipids and glycolipids mediate proton containment and circulation along the surface of energy-transducing membranes Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-07-20 Marcos Y. Yoshinaga, Matthias Y. Kellermann, David L. Valentine, Raymond C. Valentine
Proton bioenergetics provides the energy for growth and survival of most organisms in the biosphere ranging from unicellular marine phytoplankton to humans. Chloroplasts harvest light and generate a proton electrochemical gradient (proton motive force) that drives the production of ATP needed for carbon dioxide fixation and plant growth. Mitochondria, bacteria and archaea generate proton motive force to energize growth and other physiologies. Energy transducing membranes are at the heart of proton bioenergetics and are responsible for catalyzing the conversion of energy held in high-energy electrons → electron transport chain → proton motive force → ATP. Whereas the electron transport chain is understood in great detail there are major gaps in understanding mechanisms of proton transfer or circulation during proton bioenergetics. This paper is built on the proposition that phospho- and glyco-glycerolipids form proton transport circuitry at the membrane's surface. By this proposition, an emergent membrane property, termed the hyducton, confines active/unbound protons or hydronium ions to a region of low volume close to the membrane surface. In turn, a von Grotthuß mechanism rapidly moves proton substrate in accordance with nano-electrochemical poles on the membrane surface created by powerful proton pumps such as ATP synthase.
Fat type in phytosterol products influence their cholesterol-lowering potential: A systematic review and meta-analysis of RCTs Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-08-04 Jessica J.A. Ferguson, Elizabeth Stojanovski, Lesley MacDonald-Wicks, Manohar L. Garg
The most common form of phytosterol (PS) fortified foods are fat spreads and dairy products. The predominant fats used are soybean/sunflower (SS) or rapeseed/canola (RC) oils and animal fat (D) in dairy products. This review aimed to investigate whether the carrier fat is a determinant of the hypocholesterolaemic effects of PS fortified foods. Databases were searched using relevant keywords and published RCTs from 1990 investigating the effects of dietary PS intervention (≥ 1.5 g per day) on total cholesterol and LDL-C were included. After methodological quality assessment and data extraction, a total of 32 RCTs (RC, n = 15; SS, n = 9; D, n = 8) were included. As expected, all fat groups significantly reduced TC and LDL-C (p < 0.01). When compared across different carrier fats, RC as the main carrier fat, reduced LDL-C significantly more than the SS spreads (p = 0.01). Therefore, a combination of monounsaturated fatty acid rich spread with adequate amounts of omega-3 fatty acids (as evident in RC spreads) may be the superior carrier fat for the delivery of PS for optimal blood cholesterol-lowering. The findings of this research provide useful evidence for optimising the hypocholesterolaemic effects of PS and support further investigation into the possible mechanisms behind these findings.
Metabolism and functional effects of plant-derived omega-3 fatty acids in humans Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-08-03 Ella J. Baker, Elizabeth A. Miles, Graham C. Burdge, Parveen Yaqoob, Philip C. Calder
Alpha-linolenic acid (ALA) is an essential fatty acid and the substrate for the synthesis of longer-chain, more unsaturated ω-3 fatty acids, eicosapentaenoic acid (EPA), docosapentaenoic acid and docosahexaenoic acid (DHA). EPA and DHA are associated with human health benefits. The primary source of EPA and DHA is seafood. There is a need for sustainable sources of biologically active ω-3 fatty acids. Certain plants contain high concentrations of ALA and stearidonic acid (SDA). Here we review the literature on the metabolism of ALA and SDA in humans, the impact of increased ALA and SDA consumption on concentrations of EPA and DHA in blood and cell lipid pools, and the extent to which ALA and SDA might have health benefits. Although it is generally considered that humans have limited capacity for conversion of ALA to EPA and DHA, sex differences in conversion to DHA have been identified. If conversion of ALA to EPA and DHA is limited, then ALA may have a smaller health benefit than EPA and DHA. SDA is more readily converted to EPA and appears to offer better potential for health improvement than ALA. However, conversion of both ALA and SDA to DHA is limited in most humans.
Lipases from the genus Rhizopus: Characteristics, expression, protein engineering and application Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-08-04 Xiao-Wei Yu, Yan Xu, Rong Xiao
Lipases are versatile catalysts that hydrolyze ester bonds of water-insoluble glycerides or carry out reversible reactions at the water/lipid interface. The remarkable characteristics of lipases from the genus Rhizopus are their high sn-1,3-positional specificity, enantioselectivity and activity in nonaqueous media, which make them one of the most desirable enzymes for many applications, including lipid modification and biodiesel and chiral organic compound synthesis. sn-1,3-Position-specific Rhizopus lipases are particularly useful for the production of structured triacylglycerols. Significant progress has been made regarding lipases from the genus Rhizopus, including gene sequencing, elucidation of the protein structure and catalytic function, heterologous expression and redesigning Rhizopus lipases for valuable properties, which is receiving increasing academic and industrial attention. In this review, we present a comprehensive overview of Rhizopus lipases, focusing on (a) the characteristics of Rhizopus lipases, (b) Rhizopus lipase genes and structural features, (c) strategies for heterologous expression of Rhizopus lipase genes in yeast system, (d) progress in protein engineering for the improvement of the properties of Rhizopus lipases, and (e) development of biotechnological applications.
Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-08-12 Thomas Günther Pomorski, Anant K. Menon
Membrane lipids diffuse rapidly in the plane of the membrane but their ability to flip spontaneously across a membrane bilayer is hampered by a significant energy barrier. Thus spontaneous flip-flop of polar lipids across membranes is very slow, even though it must occur rapidly to support diverse aspects of cellular life. Here we discuss the mechanisms by which rapid flip-flop occurs, and what role lipid flipping plays in membrane homeostasis and cell growth. We focus on conceptual aspects, highlighting mechanistic insights from biochemical and in silico experiments, and the recent, ground-breaking identification of a number of lipid scramblases.
Evolution of the diacylglycerol lipases Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-08-26 Dongjuan Yuan, Zhongdao Wu, Yonghua Wang
Diacylglycerol lipases (DGLs) mainly catalyze “on-demand” biosynthesis of bioactive monoacylglycerols (MAGs) with different long fatty acyl chains, including 2-arachidonoylglycerol (2-AG), 2-linoleoylglycerol (2-LG), 2-oleoylglycerol (2-OG) and 2-palmitoylglycerol (2-PG). Enzymatic characterization of DGLs, their expression and distribution, and functional features has been elucidated from microorganisms to mammals in some extent. In mammals, biosynthesis, degradation and metabolism of these bioactive lipids intertwine and form a complicated biochemical pathway to affect the mammal neuromodulation of central nervous system and also other physiological processes in most peripheral organs and non-nervous tissue cells, and yet we still do not know if the neuromodulatory role of mammal DGL and MAGs is similar to invertebrates. Tracing the evolutionary history of DGLs from microorganisms to vertebrates will be an essential method to infer DGL and MAG research in organisms. In this review, we give an exhaustive explanation of the ancestral origin, divergence and evolutionary pattern through systemic searching of DGL orthologs in different species. Finally, we also summarize our recent work on the structural and functional studies of DGL in order to explore usage of DGLs in industry and the development of inhibitors for clinical intervention.
Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-10-01 Miguel A. Martín-Acebes, Ángela Vázquez-Calvo, Juan-Carlos Saiz
Flaviviruses are emerging arthropod-borne pathogens that cause life-threatening diseases such as yellow fever, dengue, West Nile encephalitis, tick-borne encephalitis, Kyasanur Forest disease, tick-borne encephalitis, or Zika disease. This viral genus groups > 50 viral species of small enveloped plus strand RNA virus that are phylogenetically closely related to hepatitis C virus. Importantly, the flavivirus life cycle is intimately associated to host cell lipids. Along this line, flaviviruses rearrange intracellular membranes from the endoplasmic-reticulum of the infected cells to develop adequate platforms for viral replication and particle biogenesis. Moreover, flaviviruses dramatically orchestrate a profound reorganization of the host cell lipid metabolism to create a favorable environment for viral multiplication. Consistently, recent work has shown the importance of specific lipid classes in flavivirus infections. For instances, fatty acid synthesis is linked to viral replication, phosphatidylserine and phosphatidylethanolamine are involved on the entry of flaviviruses, sphingolipids (ceramide and sphingomyelin) play a key role on virus assembly and pathogenesis, and cholesterol is essential for innate immunity evasion in flavivirus-infected cells. Here, we revise the current knowledge on the interactions of the flaviviruses with the cellular lipid metabolism to identify potential targets for future antiviral development aimed to combat these relevant health-threatening pathogens.
DHCR7: A vital enzyme switch between cholesterol and vitamin D production Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-09-30 Anika V. Prabhu, Winnie Luu, Dianfan Li, Laura J. Sharpe, Andrew J. Brown
The conversion of 7-dehydrocholesterol to cholesterol, the final step of cholesterol synthesis in the Kandutsch-Russell pathway, is catalyzed by the enzyme 7-dehydrocholesterol reductase (DHCR7). Homozygous or compound heterozygous mutations in DHCR7 lead to the developmental disease Smith-Lemli-Opitz syndrome, which can also result in fetal mortality, highlighting the importance of this enzyme in human development and survival. Besides serving as a substrate for DHCR7, 7-dehydrocholesterol is also a precursor of vitamin D via the action of ultraviolet light on the skin. Thus, DHCR7 exerts complex biological effects, involved in both cholesterol and vitamin D production. Indeed, we argue that DHCR7 can act as a switch between cholesterol and vitamin D synthesis. This review summarizes current knowledge about the critical enzyme DHCR7, highlighting recent findings regarding its structure, transcriptional and post-transcriptional regulation, and its links to vitamin D synthesis. Greater understanding about DHCR7 function, regulation and its place within cellular metabolism will provide important insights into its biological roles.
Oxysterols: From cholesterol metabolites to key mediators Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-09-26 Valentin Mutemberezi, Owein Guillemot-Legris, Giulio G. Muccioli
Oxysterols are cholesterol metabolites that can be produced through enzymatic or radical processes. They constitute a large family of lipids (i.e. the oxysterome) involved in a plethora of physiological processes. They can act through GPCR (e.g. EBI2, SMO, CXCR2), nuclear receptors (LXR, ROR, ERα) and through transporters or regulatory proteins. Their physiological effects encompass cholesterol, lipid and glucose homeostasis. Additionally, they were shown to be involved in other processes such as immune regulatory functions and brain homeostasis. First studied as precursors of bile acids, they quickly emerged as interesting lipid mediators. Their levels are greatly altered in several pathologies and some oxysterols (e.g. 4β-hydroxycholesterol or 7α-hydroxycholestenone) are used as biomarkers of specific pathologies. In this review, we discuss the complex metabolism and molecular targets (including binding properties) of these bioactive lipids in human and mice. We also discuss the genetic mouse models currently available to interrogate their effects in pathophysiological settings. We also summarize the levels of oxysterols reported in two key organs in oxysterol metabolism (liver and brain), plasma and cerebrospinal fluid. Finally, we consider future opportunities and directions in the oxysterol field in order to gain a better insight and understanding of the complex oxysterol system.
A brief glimpse at CTRP3 and CTRP9 in lipid metabolism and cardiovascular protection Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-10-12 Yang Yang, Yue Li, Zhiqiang Ma, Shuai Jiang, Chongxi Fan, Wei Hu, Dongjin Wang, Shouyin Di, Yang Sun, Wei Yi
Adipose tissue is now known to express and secrete numerous adipokines that not only regulate lipid metabolism but also function in a wide array of physiological or pathological processes. C1q tumor necrosis factor-related protein 3 (CTRP3, also known as CORS26/cartducin) and CTRP9, novel members of the adipokine family, have intersecting functions in the regulation of lipid metabolism and contribute to cardiovascular protection. Here, we focus on the novel advances concerning the roles of CTRP3 and CTRP9 in these processes and review the general mechanisms. This review should serve as a basis for the design of future experimental studies and may implicate these adipokines as future therapeutic targets.
The role of DNA methylation in dyslipidaemia: A systematic review Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-10-13 Kim V.E. Braun, Trudy Voortman, Klodian Dhana, Jenna Troup, Wichor M. Bramer, John Troup, Rajiv Chowdhury, Abbas Dehghan, Taulant Muka, Oscar H. Franco
Epigenetic mechanisms, including DNA methylation and histone modifications, might be involved in the regulation of blood lipid concentration variability and may thereby affect cardiovascular health. We aimed to systematically review studies investigating the association between epigenetic marks and plasma concentrations of triacylglycerol, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Six medical databases were searched until September 3rd 2015, reference lists were screened, and experts in the field were contacted. Of the 757 identified references, 31 articles reporting on 23 unique studies met all inclusion criteria. These studies included data on 8027 unique participants. Overall, no consistent associations were observed between global DNA methylation and blood lipids. Candidate gene and epigenome-wide association studies reported epigenetic regulation of several genes to be related with blood lipids, of which results for ABCG1, CPT1A, TNNT1, MIR33B, SREBF1, and TNIP were replicated. To date, no studies have been performed on histone modification in relation to blood lipids. To conclude, promising results have been reported in the field of epigenetics and dyslipidaemia, however, further rigorous studies are needed to expand our understanding on the role of epigenetics in regulating human's blood lipid levels and its effects on health and disease.
Liposomal systems as viable drug delivery technology for skin cancer sites with an outlook on lipid-based delivery vehicles and diagnostic imaging inputs for skin conditions' Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-09-30 Naseem Akhtar, Riaz A. Khan
Skin cancer is among one of the most common human malignancies wide-spread world-over with mortality statistics rising continuously at an alarming rate. The increasing frequency of these malignancies has marked the need for adopting effective treatment plan coupled with better and site-specific delivery options for the desired therapeutic agent's availability at the affected site. The concurrent delivery approaches to cancerous tissues are under constant challenge and, as a result, are evolving and gaining advancements in terms of delivery modes, therapeutic agents and site-specificity of the therapeutics delivery. The lipid-based liposomal drug delivery is an attractive and emerging option, and which is meticulously shaping up beyond a threshold level to a promising, and viable route for the effective delivery of therapeutic agents and other required injuctions to the skin cancer. An update on liposomal delivery of chemotherapeutic agents, natural-origin compounds, photosensitizer, and DNA repair enzymes as well as other desirable and typical delivery modes employed in drug delivery and in the treatment of skin cancers is discussed in details. Moreover, liposomal delivery of nucleic acid-based therapeutics, i.e., small interfering RNA (siRNA), mRNA therapy, and RGD-linked liposomes are among the other promising novel technology under constant development. The current clinical applicability, viable clinical plans, future prospects including transport feasibility of delivery vesicles and imaging techniques in conjunction with the therapeutic agents is also discussed. The ongoing innovations in liposomal drug delivery technology for skin cancers hold promise for further development of the methodology for better, more effective and site-specific delivery as part of the better treatment plan by ensuring faster drug transport, better and full payload delivery with enough and required concentration of the dose.
Structure and functionality of nanostructured triacylglycerol crystal networks Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-10-01 Pere R. Ramel, Edmund D. Co, Nuria C. Acevedo, Alejandro G. Marangoni
From hopanoids to cholesterol: Molecular clocks of pentameric ligand-gated ion channels Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-04-12 Francisco J. Barrantes, Jacques Fantini
Pentameric ligand-gated ion channels (pLGICs) and their lipid microenvironments appear to have acquired mutually adaptive traits along evolution: 1) the three-ring architecture of their transmembrane (TM) region; 2) the ability of the outermost TM ring to convey lipid signals to the middle ring, which passes them on to the central pore ring, and 3) consensus motifs for sterol recognition in all pLGICs. Hopanoids are triterpenoid fossil lipids that constitute invaluable biomarkers for tracing evolution at the molecular scale. The cyanobacterium Gloeobacter violaceus is the oldest known living organism in which the X-ray structure of its pLGIC, GLIC, reveals the presence of the above attributes and, as discussed in this review, the ability to bind hopanoids. ELIC, the pLGIC from the bacillus Erwinia chrysanthemi is the only other known case to date. Both prokaryotes lack cholesterol but their pLGICs exhibit the same sterol motifs as mammalian pLGIC. This remarkable conservation suggests that the association of sterols and hopanoid surrogate molecules arose from the early need in prokaryotes to stabilize pLGIC TM regions by means of relatively rigid lipid molecules. The conservation of these phenotypic traits along such a long phylogenetic span leads us to suggest the possible co-evolution of these sterols with pLGICs.
Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-04-09 Elisabetta Damiani, Stephen E. Ullrich
Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome.
Choline kinase alpha—Putting the ChoK-hold on tumor metabolism ☆ Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-04-09 Sean P. Arlauckas, Anatoliy V. Popov, E. James Delikatny
It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.
Mechanism of fat taste perception: Association with diet and obesity Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-05-05 Dongli Liu, Nicholas Archer, Konsta Duesing, Garry Hannan, Russell Keast
Energy homeostasis plays a significant role in food consumption and body weight regulation with fat intake being an area of particular interest due to its palatability and high energy density. Increasing evidence from humans and animal studies indicate the existence of a taste modality responsive to fat via its breakdown product fatty acids. These studies implicate multiple candidate receptors and ion channels for fatty acid taste detection, indicating a complex peripheral physiology that is currently not well understood. Additionally, a limited number of studies suggest a reduced ability to detect fatty acids is associated with obesity and a diet high in fat reduces an individual's ability to detect fatty acids. To support this, genetic variants within candidate fatty acid receptors are also associated with obesity reduced ability to detect fatty acids. Understanding oral peripheral fatty acid transduction mechanisms and the association with fat consumption may provide the basis of novel approaches to control development of obesity.
Synthesis and degradation pathways, functions, and pathology of ceramides and epidermal acylceramides Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-04-21 Akio Kihara
Ceramide (Cer) is a structural backbone of sphingolipids and is composed of a long-chain base and a fatty acid. Existence of a variety of Cer species, which differ in chain-length, hydroxylation status, and/or double bond number of either of their hydrophobic chains, has been reported. Ceramide is produced by Cer synthases. Mammals have six Cer synthases (CERS1–6), each of which exhibits characteristic substrate specificity toward acyl-CoAs with different chain-lengths. Knockout mice for each Cer synthase show corresponding, isozyme-specific phenotypes, revealing the functional differences of Cers with different chain-lengths. Cer diversity is especially prominent in epidermis. Changes in Cer levels, composition, and chain-lengths are associated with atopic dermatitis. Acylceramide (acyl-Cer) specifically exists in epidermis and plays an essential role in skin permeability barrier formation. Accordingly, defects in acyl-Cer synthesis cause the cutaneous disorder ichthyosis with accompanying severe skin barrier defects. Although the molecular mechanism by which acyl-Cer is generated was long unclear, most genes involved in its synthesis have been identified recently. In Cer degradation pathways, the long-chain base moiety of Cer is converted to acyl-CoA, which is then incorporated mainly into glycerophospholipids. This pathway generates the lipid mediator sphingosine 1-phosphate. This review will focus on recent advances in our understanding of the synthesis and degradation pathways, physiological functions, and pathology of Cers/acyl-Cers.
Isoprenoid generating systems in plants — A handy toolbox how to assess contribution of the mevalonate and methylerythritol phosphate pathways to the biosynthetic process Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-04-29 Agata Lipko, Ewa Swiezewska
Isoprenoids comprise an astonishingly diverse group of metabolites with numerous potential and actual applications in medicine, agriculture and the chemical industry. Generation of efficient platforms producing isoprenoids is a target of numerous laboratories. Such efforts are generally enhanced if the native biosynthetic routes can be identified, and if the regulatory mechanisms responsible for the biosynthesis of the compound(s) of interest can be determined.In this review a critical summary of the techniques applied to establish the contribution of the two alternative routes of isoprenoid production operating in plant cells, the mevalonate and methylerythritol pathways, with a focus on their co-operation (cross-talk) is presented. Special attention has been paid to methodological aspects of the referred studies, in order to give the reader a deeper understanding for the nuances of these powerful techniques. This review has been designed as an organized toolbox, which might offer the researchers comments useful both for project design and for interpretation of results obtained.
The enigma of ceramide synthase regulation in mammalian cells Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-05-13 Marthe-Susanna Wegner, Susanne Schiffmann, Michael John Parnham, Gerd Geisslinger, Sabine Grösch
Ceramide synthases (CerS) are key enzymes in the lipid metabolism of eukaryotic cells. Their products, ceramides (Cer), are components of cellular membranes but also mediate signaling functions in physiological processes such as proliferation, skin barrier function and cerebellar development. In pathophysiological processes such as multiple sclerosis and tumor progression, ceramide levels are altered, which can be ascribed, partly, to dysregulation of CerS gene transcription. Most publications deal with the effects of altered ceramide levels on physiological and pathophysiological processes, but the regulation of the appropriate CerS is frequently not investigated. This is insufficient for the clarification of the role of ceramides, because most ceramide species are generated by at least two CerS. The mechanisms of CerS regulation are manifold and it seems that each CerS isoform is regulated individually. For this reason, we discuss the different CerS separately in this review. From transcriptional regulation to alteration of protein activity, the possibilities to influence CerS are diverse. Furthermore, CerS are influenced by a variety of molecules including hormones and lipids. Without claiming completeness, we provide a résumé of the regulatory mechanisms for each CerS in mammalian cells and how dysregulation of these mechanisms during physiological processes may lead to pathophysiological processes.
Fatty acylation of proteins: The long and the short of it Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-05-24 Marilyn D. Resh
Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.
Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-05-20 Ken D. Stark, Mary E. Van Elswyk, M. Roberta Higgins, Charli A. Weatherford, Norman Salem Jr.
Engineering and application of enzymes for lipid modification, an update Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-06-11 Katja Zorn, Isabel Oroz-Guinea, Henrike Brundiek, Uwe T. Bornscheuer
This review first provides a brief introduction into the most important tools and strategies for protein engineering (i.e. directed evolution and rational protein design combined with high-throughput screening methods) followed by examples from literature, in which enzymes have been optimized for biocatalytic applications. This covers engineered lipases with altered fatty acid chain length selectivity, fatty acid specificity and improved performance in esterification reactions. Furthermore, recent achievements reported for phospholipases, lipoxygenases, P450 monooxygenases, decarboxylating enzymes, fatty acid hydratases and the use of enzymes in cascade reactions are treated.
Plant acyl-CoA-binding proteins: An emerging family involved in plant development and stress responses Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-06-29 Zhi-Yan Du, Tatiana Arias, Wei Meng, Mee-Len Chye
Acyl-CoA-binding protein (ACBP) was first identified in mammals as a neuropeptide, and was demonstrated to belong to an important house-keeping protein family that extends across eukaryotes and some prokaryotes. In plants, the Arabidopsis ACBP family consists of six AtACBPs (AtACBP1 to AtACBP6), and has been investigated using gene knock-out mutants and overexpression lines. Herein, recent findings on the AtACBPs are examined to provide an insight on their functions in various plant developmental processes, such as embryo and seed development, seed dormancy and germination, seedling development and cuticle formation, as well as their roles under various environmental stresses. The significance of the AtACBPs in acyl-CoA/lipid metabolism, with focus on their interaction with long to very-long-chain (VLC) acyl-CoA esters and their potential role in the formation of lipid droplets in seeds and vegetative tissues are discussed. In addition, recent findings on the rice ACBP family are presented. The similarities and differences between ACBPs from Arabidopsis and rice, that represent eudicot and monocot model plants, respectively, are analyzed and the evolution of plant ACBPs by phylogenetic analysis reviewed. Finally, we propose potential uses of plant ACBPs in phytoremediation and in agriculture related to the improvement of environmental stress tolerance and seed oil production.
Recent progress on lipid lateral heterogeneity in plasma membranes: From rafts to submicrometric domains Prog. Lipid. Res. (IF 10.583) Pub Date : 2015-12-29 Mélanie Carquin, Ludovic D’Auria, Hélène Pollet, Ernesto R. Bongarzone, Donatienne Tyteca
The concept of transient nanometric domains known as lipid rafts has brought interest to reassess the validity of the Singer–Nicolson model of a fluid bilayer for cell membranes. However, this new view is still insufficient to explain the cellular control of surface lipid diversity or membrane deformability. During the past decades, the hypothesis that some lipids form large (submicrometric/mesoscale vs nanometric rafts) and stable (> min vs s) membrane domains has emerged, largely based on indirect methods. Morphological evidence for stable submicrometric lipid domains, well-accepted for artificial and highly specialized biological membranes, was further reported for a variety of living cells from prokaryot es to yeast and mammalian cells. However, results remained questioned based on limitations of available fluorescent tools, use of poor lipid fixatives, and imaging artifacts due to non-resolved membrane projections. In this review, we will discuss recent evidence generated using powerful and innovative approaches such as lipid-specific toxin fragments that support the existence of submicrometric domains. We will integrate documented mechanisms involved in the formation and maintenance of these domains, and provide a perspective on their relevance on membrane deformability and regulation of membrane protein distribution.
Long-chain polyunsaturated fatty acid biosynthesis in chordates: Insights into the evolution of Fads and Elovl gene repertoire Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-01-06 L. Filipe C. Castro, Douglas R. Tocher, Oscar Monroig
Long-chain polyunsaturated fatty acids (LC-PUFA) are major components of complex lipid molecules and are also involved in numerous critical biological processes. Studies conducted mainly in vertebrates have demonstrated that LC-PUFA can be biosynthesized through the concerted action of two sets of enzymes, namely fatty acyl desaturases (Fads) and elongation of very long-chain fatty acid (Elovl) proteins. While LC-PUFA research is a thriving field, mainly focused on human health, an integrated view regarding the evolution of LC-PUFA biosynthetic genetic machinery in chordates is yet to be produced. Particularly important is to understand whether lineage specific life history trajectories, as well as major biological transitions, or particular genomic processes such as genome duplications have impacted the evolution of LC-PUFA biosynthetic pathways. Here we review the gene repertoire of Fads and Elovl in chordate genomes and the diversity of substrate specificities acquired during evolution. We take advantage of the magnitude of genomic and functional data to show that combination duplication processes and functional plasticity have generated a wide diversity of physiological capacities in extant lineages. A clear evolutionary framework is provided, which will be instrumental for the full clarification of functional capacities between the various vertebrate groups.
The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: Acting separately or synergistically? Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-01-04 Cai Song, Chu-Hsin Shieh, Yi-Shyuan Wu, Allan Kalueff, Siddharth Gaikwad, Kuan-Pin Su
Omega-3 polyunsaturated fatty acids (n‐3-PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may improve or prevent some psychiatric and neurodegenerative diseases in both experimental and clinical studies. As important membrane components, these PUFAs benefit brain health by modulating neuroimmune and apoptotic pathways, changing membrane function and/or competing with n‐6 PUFAs, the precursors of inflammatory mediators. However, the exact role of each fatty acid in neuroimmune modulation and neurogenesis, the interaction between EPA and DHA, and the best EPA:DHA ratios for improving brain disorders, remain unclear. It is also unknown whether EPA, as a DHA precursor, acts directly or via DHA. Here, we discuss recent evidence of EPA and DHA effects in the treatment of major depression and Alzheimer's disease, as well as their potential synergistic action on anti-inflammatory, antioxidant and neurotrophic processes in the brain. We further analyze the cellular and molecular mechanisms by which EPA, DHA or their combination may benefit these diseases. We also outline the limitations of current studies and suggest new genetic models and novel approaches to overcome these limitations. Finally, we summarize future strategies for translational research in this field.
Plant phospholipases D and C and their diverse functions in stress responses Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-01-16 Yueyun Hong, Jian Zhao, Liang Guo, Sang-Chul Kim, Xianjun Deng, Geliang Wang, Gaoyang Zhang, Maoyin Li, Xuemin Wang
Phospholipases D (PLD) and C (PLC) hydrolyze the phosphodiesteric linkages of the head group of membrane phospholipids. PLDs and PLCs in plants occur in different forms: the calcium-dependent phospholipid binding domain-containing PLDs (C2-PLDs), the plekstrin homology and phox homology domain-containing PLDs (PX/PH-PLDs), phosphoinositide-specific PLC (PI-PLC), and non-specific PLC (NPC). They differ in structures, substrate selectivities, cofactor requirements, and/or reaction conditions. These enzymes and their reaction products, such as phosphatidic acid (PA), diacylglycerol (DAG), and inositol polyphosphates, play important, multifaceted roles in plant response to abiotic and biotic stresses. Here, we review biochemical properties, cellular effects, and physiological functions of PLDs and PLCs, particularly in the context of their roles in stress response along with advances made on the role of PA and DAG in cell signaling in plants. The mechanism of actions, including those common and distinguishable among different PLDs and PLCs, will also be discussed.
Roles of specific lipid species in the cell and their molecular mechanism Prog. Lipid. Res. (IF 10.583) Pub Date : 2016-02-11 Tomohiro Kimura, William Jennings, Richard M. Epand
Thousands of different molecular species of lipids are present within a single cell, being involved in modulating the basic processes of life. The vast number of different lipid species can be organized into a number of different lipid classes, which may be defined as a group of lipids with a common chemical structure, such as the headgroup, apart from the nature of the hydrocarbon chains. Each lipid class has unique biological roles. In some cases, a relatively small change in the headgroup chemical structure can result in a drastic change in function. Such phenomena are well documented, and largely understood in terms of specific interactions with proteins. In contrast, there are observations that the entire structural specificity of a lipid molecule, including the hydrocarbon chains, is required for biological activity through specific interactions with membrane proteins. Understanding of these phenomena represents a fundamental change in our thinking of the functions of lipids in biology. There are an increasing number of diverse examples of roles for specific lipids in cellular processes including: Signal transduction; trafficking; morphological changes; cell division. We are gaining knowledge and understanding of the underlying molecular mechanisms. They are of growing importance in both basic and applied sciences.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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