Progress in lipid research最新文献

MDD (major depressive disorder) is a highly prevalent mental disorder with a complex etiology involving behavioral and neurochemical factors as well as environmental stress. The interindividual variability in response to stress stimuli may be explained by processes such as long-term potentiation (LTP) and long-term depression (LTD). LTP can be described as the strengthening of synaptic transmission, which translates into more efficient cognitive performance and is regulated by brain-derived neurotrophic factor (BDNF), a protein responsible for promoting neural growth. It is found in high concentrations in the hippocampus, a part of the limbic system which is far less active in people with MDD. Omega-3 fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) not only contribute to structural and antioxidative functions but are essential for the maintenance of LTP and stable BDNF levels. This review explores the mechanisms and potential roles of omega-3 fatty acids in the prevention of MDD.

The barrier function of the skin is primarily located in the stratum corneum (SC), the outermost layer of the skin. The SC is composed of dead cells with highly organized lipid lamellae in the intercellular space. As the lipid matrix forms the only continuous pathway, the lipids play an important role in the permeation of compounds through the SC. The main lipid classes are ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). Analysis of the SC lipid matrix is of crucial importance in understanding the skin barrier function, not only in healthy skin, but also in inflammatory skin diseases with an impaired skin barrier. In this review we provide i) a historical overview of the steps undertaken to obtain information on the lipid composition and organization in SC of healthy skin and inflammatory skin diseases, ii) information on the role CERs, CHOL and FFAs play in the lipid phase behavior of very complex lipid model systems and how this knowledge can be used to understand the deviation in lipid phase behavior in inflammatory skin diseases, iii) knowledge on the role of both, CER subclasses and chain length distribution, on lipid organization and lipid membrane permeability in complex and simple model systems with synthetic CERs, CHOL and FFAs, iv) similarity in lipid phase behavior in SC of different species and complex model systems, and vi) future directions in modulating lipid composition that is expected to improve the skin barrier in inflammatory skin diseases.

The unique biophysical and biochemical properties of lipids render them crucial in most models of the origin of life (OoL). Many studies have attempted to delineate the prebiotic pathways by which lipids were formed, how micelles and vesicles were generated, and how these micelles and vesicles became selectively permeable towards the chemical precursors required to initiate and support biochemistry and inheritance. Our analysis of a number of such studies highlights the extremely narrow and limited range of conditions by which an experiment is considered to have successfully modeled a role for lipids in an OoL experiment. This is in line with a recent proposal that bias is introduced into OoL studies by the extent and the kind of human intervention. It is self-evident that OoL studies can only be performed by human intervention, and we now discuss the possibility that some assumptions and simplifications inherent in such experimental approaches do not permit determination of mechanistic insight into the roles of lipids in the OoL. With these limitations in mind, we suggest that more nuanced experimental approaches than those currently pursued may be required to elucidate the generation and function of lipids, micelles and vesicles in the OoL.

Sphingolipids are essential components of all eukaryotic membranes. The bioactive sphingolipid molecule, Sphingosine 1-Phosphate (S1P), regulates various important biological functions. This review aims to provide a comprehensive overview of the role of S1P signaling pathway in various immune cell functions under different pathophysiological conditions including bacterial and viral infections, autoimmune disorders, inflammation, and cancer. We covered the aspects of S1P pathways in NOD/TLR pathways, bacterial and viral infections, autoimmune disorders, and tumor immunology. This implies that targeting S1P signaling can be used as a strategy to block these pathologies. Our current understanding of targeting various components of S1P signaling for therapeutic purposes and the present status of S1P pathway inhibitors or modulators in disease conditions where the host immune system plays a pivotal role is the primary focus of this review.

Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various particles, including lipids. Defective lipid handling can drive excessive lipid accumulation leading to foam cell formation, a key feature of various cardiometabolic conditions such as atherosclerosis, non-alcoholic fatty liver disease, and obesity. At the same time, intracellular lipid storage and foam cell formation can also be viewed as a protective and anti-lipotoxic mechanism against a lipid-rich environment and associated elevated lipid uptake. Traditionally, foam cell formation has primarily been linked to cholesterol uptake via native and modified low-density lipoproteins. However, other lipids, including non-esterified fatty acids and triacylglycerol (TAG)-rich lipoproteins (very low-density lipoproteins and chylomicrons), can also interact with macrophages. Recent studies have identified multiple pathways mediating TAG uptake and processing by macrophages, including endocytosis and receptor/transporter-mediated internalization and transport. This review will present the current knowledge of how macrophages take up different lipids and lipoprotein particles and address how TAG-rich lipoproteins are processed intracellularly. Understanding how macrophages take up and process different lipid species such as TAG is necessary to design future therapeutic interventions to correct excessive lipid accumulation and associated co-morbidities.

Dysregulation of fatty acid metabolism and de novo lipogenesis is a key driver of several cancer types through highly unsaturated fatty acid (HUFA) signaling precursors such as arachidonic acid. The human chromosome 11q13 locus has long been established as the most frequently amplified in a variety of human cancers. The fatty acid desaturase genes (FADS1, FADS2 and FADS3) responsible for HUFA biosynthesis localize to the 11q12-13.1 region. FADS2 activity is promiscuous, catalyzing biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation. Our main aim here is to review known and putative consequences of FADS2 dysregulation due to effects on the 11q13 locus potentially driving various cancer types. FADS2 silencing causes synthesis of sciadonic acid (5Z,11Z,14Z-20:3) in MCF7 cells and breast cancer in vivo. 5Z,11Z,14Z-20:3 is structurally identical to arachidonic acid (5Z,8Z,11Z,14Z–20:4) except it lacks the internal Δ8 double bond required for prostaglandin and leukotriene synthesis, among other eicosanoids. Palmitic acid has substrate specificity for both SCD and FADS2. Melanoma, prostate, liver and lung cancer cells insensitive to SCD inhibition show increased FADS2 activity and sapienic acid biosynthesis. Elevated serum mead acid levels found in hepatocellular carcinoma patients suggest an unsatisfied demand for arachidonic acid. FADS2 circular RNAs are at high levels in colorectal and lung cancer tissues. FADS2 circular RNAs are associated with shorter overall survival in colorectal cancer patients. The evidence thusfar supports an effort for future research on the role of FADS2 as a tumor suppressor in a range of neoplastic disorders.

Mammalian lipid droplets (LDs) are specialized cytosolic organelles consisting of a neutral lipid core surrounded by a membrane made up of a phospholipid monolayer and a specific population of proteins that varies according to the location and function of each LD. Over the past decade, there have been significant advances in the understanding of LD biogenesis and functions. LDs are now recognized as dynamic organelles that participate in many aspects of cellular homeostasis plus other vital functions. LD biogenesis is a complex, highly-regulated process with assembly occurring on the endoplasmic reticulum although aspects of the underpinning molecular mechanisms remain elusive. For example, it is unclear how many enzymes participate in the biosynthesis of the neutral lipid components of LDs and how this process is coordinated in response to different metabolic cues to promote or suppress LD formation and turnover. In addition to enzymes involved in the biosynthesis of neutral lipids, various scaffolding proteins play roles in coordinating LD formation. Despite their lack of ultrastructural diversity, LDs in different mammalian cell types are involved in a wide range of biological functions. These include roles in membrane homeostasis, regulation of hypoxia, neoplastic inflammatory responses, cellular oxidative status, lipid peroxidation, and protection against potentially toxic intracellular fatty acids and lipophilic xenobiotics. Herein, the roles of mammalian LDs and their associated proteins are reviewed with a particular focus on their roles in pathological, immunological and anti-toxicological processes.

The major archaeal membrane glycerolipids are distinguished from those of bacteria and eukaryotes by the contrasting stereochemistry of their glycerol backbones, and by the use of ether-linked isoprenoid-based alkyl chains rather than ester-linked fatty acyl chains for their hydrophobic moieties. These fascinating compounds play important roles in the extremophile lifestyles of many species, but are also present in the growing numbers of recently discovered mesophilic archaea. The past decade has witnessed significant advances in our understanding of archaea in general and their lipids in particular. Much of the new information has come from the ability to screen large microbial populations via environmental metagenomics, which has revolutionised our understanding of the extent of archaeal biodiversity that is coupled with a strict conservation of their membrane lipid compositions. Significant additional progress has come from new culturing and analytical techniques that are gradually enabling archaeal physiology and biochemistry to be studied in real time. These studies are beginning to shed light on the much-discussed and still-controversial process of eukaryogenesis, which probably involved both bacterial and archaeal progenitors. Puzzlingly, although eukaryotes retain many attributes of their putative archaeal ancestors, their lipid compositions only reflect their bacterial progenitors. Finally, elucidation of archaeal lipids and their metabolic pathways have revealed potentially interesting applications that have opened up new frontiers for biotechnological exploitation of these organisms. This review is concerned with the analysis, structure, function, evolution and biotechnology of archaeal lipids and their associated metabolic pathways.

Dihydroceramide desaturase 1 (DEGS1) converts dihydroceramide (dhCer) to ceramide (Cer) by inserting a C4-C5 trans (∆4E) double bond into the sphingoid backbone. Low DEGS activity causes accumulation of dhCer and other dihydrosphingolipid species. Although dhCer and Cer are structurally very similar, their imbalances can have major consequences both in vitro and in vivo. Mutations in the human DEGS1 gene are known to cause severe neurological defects, such as hypomyelinating leukodystrophy. Likewise, inhibition of DEGS1 activity in fly and zebrafish models causes dhCer accumulation and subsequent neuronal dysfunction, suggesting that DEGS1 activity plays a conserved and critical role in the nervous system. Dihydrosphingolipids and their desaturated counterparts are known to control various essential processes, including autophagy, exosome biogenesis, ER stress, cell proliferation, and cell death. Furthermore, model membranes with either dihydrosphingolipids or sphingolipids exhibit different biophysical properties, including membrane permeability and packing, thermal stability, and lipid diffusion. However, the links between molecular properties, in vivo functional data, and clinical manifestations that underlie impaired DEGS1 function remain largely unresolved. In this review, we summarize the known biological and pathophysiological roles of dhCer and its derivative dihydrosphingolipid species in the nervous system, and we highlight several possible disease mechanisms that warrant further investigation.

Glycosphingolipids (GSLs) are major amphiphilic glycolipids present on the surface of living cell membranes. They have important biological functions, including maintaining plasma membrane stability, regulating signal transduction, and mediating cell recognition and adhesion. Specific GSLs and related enzymes are abnormally expressed in many cancer diseases and affect the malignant characteristics of tumors. The regulatory roles of GSLs in signaling pathways suggest that they are involved in tumor pathogenesis. GSLs have therefore been widely studied as diagnostic markers of cancer diseases and important targets of immunotherapy. This review describes the tumor-related biological functions of GSLs and systematically introduces recent progress in using diverse GSLs and related enzymes to diagnose and treat tumor diseases. Development of drugs and biomarkers for personalized cancer therapy based on GSL structure is also discussed. These advances, combined with recent progress in the preparation of GSLs derivatives through synthetic biology technologies, suggest a strong future for the use of customized GSL libraries in treating human diseases.