Progress in lipid research最新文献

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.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.

Plasmalogen is a major phospholipid of mammalian cell membranes. Recently it is becoming evident that the sn-1 vinyl-ether linkage in plasmalogen, contrasting to the ester linkage in the counterpart diacyl glycerophospholipid, yields differential molecular characteristics for these lipids especially related to hydrocarbon-chain order, so as to concertedly regulate biological membrane processes. A role played by NMR in gaining information in this respect, ranging from molecular to tissue levels, draws particular attention. We note here that a broad range of enzymes in de novo synthesis pathway of plasmalogen commonly constitute that of diacyl glycerophospholipid. This fact forms the basis for systematic crosstalk that not only controls a quantitative balance between these lipids, but also senses a defect causing loss of lipid in either pathway for compensation by increase of the counterpart lipid. However, this inherent counterbalancing mechanism paradoxically amplifies imbalance in differential effects of these lipids in a diseased state on membrane processes. While sharing of enzymes has been recognized, it is now possible to overview the crosstalk with growing information for specific enzymes involved. The overview provides a fundamental clue to consider cell and tissue type-dependent schemes in regulating membrane processes by plasmalogen and diacyl glycerophospholipid in health and disease.

Adipokines play a significant role in cardiometabolic diseases. Asprosin, a newly discovered adipokine, was first identified as a glucose-raising protein hormone. Asprosin also stimulates appetite and regulates glucose and lipid metabolism. Its identified receptors so far include Olfr734 and Ptprd. Clinical studies have found that asprosin may be associated with cardiometabolic diseases. Asprosin may have diagnostic and therapeutic potential in obesity, diabetes, metabolic syndrome and atherosclerotic cardiovascular diseases. Herein, the structure, receptors, and functions of asprosin and its relationship with cardiometabolic diseases are summarized based on recent findings.

Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid metabolism are responsible for the development of various pathologies comprising metabolic syndrome, obesity, and type 2 diabetes. Accumulating evidence suggests that circadian oscillators, operative in most cells of our body, coordinate temporal aspects of lipid homeostasis. In this review we summarize current knowledge on the circadian regulation of lipid digestion, absorption, transportation, biosynthesis, catabolism, and storage. Specifically, we focus on the molecular interactions between functional clockwork and biosynthetic pathways of major lipid classes comprising cholesterol, fatty acids, triacylglycerols, glycerophospholipids, glycosphingolipids, and sphingomyelins. A growing body of epidemiological studies associate a socially imposed circadian misalignment common in modern society with growing incidence of metabolic disorders, however the disruption of lipid metabolism rhythms in this connection has only been recently revealed. Here, we highlight recent studies that unravel the mechanistic link between intracellular molecular clocks, lipid homeostasis and development of metabolic diseases based on animal models of clock disruption and on innovative translational studies in humans. We also discuss the perspectives of manipulating circadian oscillators as a potentially powerful approach for preventing and managing metabolic disorders in human patients.

This review is about the role of arachidonic acid (ArA) in foetal and early growth and development. In 1975 and ‘76, we reported the preferential incorporation of ArA into the developing brain of rat pups, its conservation as a principal component in the brains of 32 mammalian species and the high proportion delivered by the human placenta for foetal nutrition, compared to its parent linoleic acid (LA). ArA is quantitatively the principal acyl component of membrane lipids from foetal red cells, mononuclear cells, astrocytes, endothelium, and placenta. Functionally, we present evidence that ArA, but not DHA, relaxes the foetal mesenteric arteries. The placenta biomagnifies ArA, doubling the proportion of the maternal level in cord blood. The proportions of ArA and its allies (di-homo-gamma-linolenic acid (DGLA), adrenic acid and ω6 docosapentaenoic acid) are similar or higher than the total of ω3 fatty acids in human milk, maintaining the abundant supply to the developing infant. Despite the evidence of the importance of ArA, the European Food Standard Agency, in 2014 rejected the joint FAO and WHO recommendation on the inclusion of ArA in infant formula, although they recommended DHA. The almost universal dominance of ArA in the membrane phosphoglycerides during human organogenesis and prenatal growth suggests that the importance of ArA and its allies in reproductive biology needs to be re-evaluated urgently.

Dentate gyrus of the hippocampus continuously gives rise to new neurons, namely, adult-born granule cells, which contribute to conferring plasticity to the mature brain throughout life. Within this neurogenic region, the fate and behavior of neural stem cells (NSCs) and their progeny result from a complex balance and integration of a variety of cell-autonomous and cell-to-cell-interaction signals and underlying pathways. Among these structurally and functionally diverse signals, there are endocannabinoids (eCBs), the main brain retrograde messengers. These pleiotropic bioactive lipids can directly and/or indirectly influence adult hippocampal neurogenesis (AHN) by modulating, both positively and negatively, multiple molecular and cellular processes in the hippocampal niche, depending on the cell type or stage of differentiation. Firstly, eCBs act directly as cell-intrinsic factors, cell-autonomously produced by NSCs following their stimulation. Secondly, in many, if not all, niche-associated cells, including some local neuronal and nonneuronal elements, the eCB system indirectly modulates the neurogenesis, linking neuronal and glial activity to regulating distinct stages of AHN. Herein, we discuss the crosstalk of the eCB system with other neurogenesis-relevant signal pathways and speculate how the hippocampus-dependent neurobehavioral effects elicited by (endo)cannabinergic medications are interpretable in light of the key regulatory role that eCBs play on AHN.