Progress in lipid research最新文献

The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers.

Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.

Plasmalogens are a group of lipids mainly found in the cell membranes. They occur in anaerobic bacteria and in some protozoa, invertebrates and vertebrates, including humans. Their occurrence in plants and fungi is controversial. They can protect cells from damage by reactive oxygen species, protect other phospholipids or lipoprotein particles against oxidative stress, and have been implicated as signaling molecules and modulators of membrane dynamics. Biosynthesis in anaerobic and aerobic organisms occurs by different pathways, and the main biosynthetic pathway in anaerobic bacteria was clarified only this year (2021). Many different analytical techniques have been used for plasmalogen analysis, some of which are detailed below. These can be divided into two groups: shotgun lipidomics, or electrospray ionization mass spectrometry in combination with high performance liquid chromatography (LC-MS). The advantages and limitations of both techniques are discussed here, using examples from anaerobic bacteria to specialized mammalian (human) organs.

Long-chain polyunsaturated fatty acids (LCPUFAs) and their metabolites are considered essential factors to support bone and joint health. The n-6 PUFAs suppress the osteoblasts differentiation via increasing peroxisome proliferator-activated receptor gamma (PPARγ) expression and promoting adipogenesis while n-3 PUFAs promote osteoblastogenesis by down-regulating PPARγ and enhancing osteoblastic activity. Arachidonic acid (AA) and its metabolite prostaglandin E2 (PGE2) are key regulators of osteoclast differentiation via induction of the receptor activator of nuclear factor kappa-Β ligand (RANKL) pathway. Marine-derived n-3 LCPUFAs have been shown to inhibit osteoclastogenesis by decreasing the osteoprotegerin (OPG)/RANKL signalling pathway mediated by a reduction of pro-inflammatory PGE2 derived from AA. Omega-3 PUFAs reduce the expression of cartilage degrading enzyme matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS-5) protein, oxidative stress and thereby apoptosis via nuclear factor kappa-betta (NF-kβ) and inducible nitric oxide synthase (iNOS) pathways. In this review, a diverse range of important effects of LCPUFAs on bone cells and chondrocyte was highlighted through different mechanisms of action established by cell cultures and animal studies. This review allows a better understanding of the possible role of LCPUFAs in bone and chondrocyte metabolism as potential therapeutics in combating the pathological complications such as osteoporosis and osteoarthritis.

Non-alcoholic fatty liver disease (NAFLD) is a quickly emerging global health problem representing the most common chronic liver disease in the world. Atherosclerotic cardiovascular disease represents the leading cause of mortality in NAFLD patients. Cholesterol metabolism has a crucial role in the pathogenesis of both NAFLD and atherosclerosis. The liver is the major organ for cholesterol metabolism. Abnormal hepatic cholesterol metabolism not only leads to NAFLD but also drives the development of atherosclerotic dyslipidemia. The cholesterol level in hepatocytes reflects the dynamic balance between endogenous synthesis, uptake, esterification, and export, a process in which cholesterol is converted to neutral cholesteryl esters either for storage in cytosolic lipid droplets or for secretion as a major constituent of plasma lipoproteins, including very-low-density lipoproteins, chylomicrons, high-density lipoproteins, and low-density lipoproteins. In this review, we describe decades of research aimed at identifying key molecules and cellular players involved in each main aspect of hepatic cholesterol metabolism. Furthermore, we summarize the recent advances regarding the biological processes of hepatic cholesterol transport and its role in NAFLD and atherosclerosis.

Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the pancreatic lipase family. PLA1A specifically hydrolyzes sn-1 fatty acid of phosphatidylserine (PS) or 1-acyl-lysophosphatidylserine (1-acyl-lysoPS). PS externalized by activated cells or apoptotic cells or extracellular vesicles is a potential source of substrate for the production of unsaturated lysoPS species by PLA1A. Maturation and functions of many immune cells, such as T cells, dendritic cells, macrophages, and mast cells, can be regulated by PLA1A and lysoPS. Several lysoPS receptors, including GPR34, GPR174 and P2Y10, have been identified. High serum levels and high PLA1A expression are associated with autoimmune disorders such as Graves' disease and systemic lupus erythematosus. Increased expression of PLA1A is associated with metastatic melanomas. PLA1A may contribute to cardiometabolic disorders through mediating cholesterol transportation and producing lysoPS. Furthermore, PLA1A is necessary for hepatitis C virus assembly and can play a role in the antivirus innate immune response. This review summarizes recent findings on PLA1A expression, lysoPS and lysoPS receptors in autoimmune disorders, cancers, cardiometabolic disorders, antivirus immune responses, as well as regulations of immune cells.

Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic.

Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection.

In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality.

Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.

Vesicles, generally defined as self-assembled structures formed by single or multiple concentric bilayers that surround an aqueous core, have been widely used for biomedical applications. They can either occur naturally (e.g. exosomes) or be produced artificially and range from the micrometric scale to the nanoscale. One the most well-known vesicle is the liposome, largely employed as a drug delivery nanocarrier. Liposomes have been modified along the years to improve physicochemical and biological features, resulting in long-circulating, ligand-targeted and stimuli-responsive liposomes, among others. In this process, new nomenclatures were reported in an extensive literature. In many instances, the new names suggest the emergence of a new nanocarrier, which have caused confusion as to whether the vesicles are indeed new entities or could simply be considered modified liposomes. Herein, we discussed the extensive nomenclature of vesicles based on the suffix “some” that are employed for drug delivery and composed of various types and proportions of lipids and others amphiphilic compounds. New names have most often been selected based on changes of vesicle lipid composition, but the payload, structural complexity (e.g. multicompartment) and new/improved proprieties (e.g. elasticity) have also inspired new vesicle names. Based on this discussion, we suggested a rational classification for vesicles.

Pine nut oil (PNO) is rich in a variety of unusual delta-5-non-methylene-interrupted fatty acids (NMIFAs), including pinolenic acid (PLA; all cis-5,-9,-12 18:3) which typically comprises 14 to 19% of total fatty acids. PLA has been shown to be metabolised to eicosatrienoic acid (ETA; all cis-7,-11,-14 20:3) in various cells and tissues. Here we review the literature on PNO, PLA and its metabolite ETA in the context of human health applications. PNO and PLA have a range of favourable effects on body weight as well as fat deposition through increased energy expenditure (fatty acid oxidation) and decreased food energy intake (reduced appetite). PNO and PLA improve blood and hepatic lipids in animal models and insulin sensitivity in vitro and reduce inflammation and modulate immune function in vitro and in animal models. The few studies which have examined effects of ETA indicate it has anti-inflammatory properties. Another NMIFA from PNO, sciadonic acid (all cis-5,-11,-14 20:3), has generally similar properties to PLA where these have been investigated. There is potential for human health benefits from PNO, its constituent NMIFA PLA and the PLA derivative ETA. However further studies are needed to explore the effects in humans.

Omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA, C_20-24), including eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), are involved in numerous biological processes and have a range of health benefits. Fish have long been considered as the main source of n-3 LC-PUFA in human diets. However, the capacity for endogenous biosynthesis of LC-PUFA from C₁₈ PUFA varies in fish species based on the presence, expression and activity of key enzymes including fatty acyl desaturases (Fads) and elongation of very long-chain fatty acids (Elovl) proteins. In this article, we review progress on the identified Fads and Elovl, as well as the regulatory mechanisms of LC-PUFA biosynthesis both at transcriptional and post-transcriptional levels in teleosts. The most comprehensive advances have been obtained in rabbitfish Siganus canaliculatus, a marine teleost demonstrated to have the entire pathway for LC-PUFA biosynthesis, including the roles of transcription factors hepatocyte nuclear factor 4α (Hnf4α), liver X receptor alpha (Lxrα), sterol regulatory element-binding protein 1 (Srebp-1), peroxisome proliferator-activated receptor gamma (Pparγ) and stimulatory protein 1 (Sp1), as well as post-transcriptional regulation by individual microRNA (miRNA) or clusters. This research has, for the first time, demonstrated the involvement of Hnf4α, Pparγ and miRNA in the regulation of LC-PUFA biosynthesis in vertebrates. The present review provides readers with a relatively comprehensive overview of the progress made into understanding LC-PUFA biosynthetic systems in teleosts, and some insights into improving endogenous LC-PUFA biosynthesis capacity aimed at reducing the dependence of aquafeeds on fish oil while maintaining or increasing flesh LC-PUFA content and the nutritional quality of farmed fish.

Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.