How do cells coordinate the diverse elements that regulate their cholesterol homeostasis? Our model postulates that membrane cholesterol forms simple complexes with bilayer phospholipids. The phospholipids in the plasma membrane are of high affinity; consequently, they are fully complexed with the sterol. This sets the resting level of plasma membrane cholesterol. Cholesterol in excess of the stoichiometric equivalence point of these complexes has high chemical activity; we refer to it as active cholesterol. It equilibrates with the low affinity phospholipids in the intracellular membranes where it serves as a negative feedback signal to a manifold of regulatory proteins that rein in ongoing cholesterol accretion. We tested the model with a review of the literature regarding fourteen homeostatic proteins in enterocytes. It provided strong albeit indirect support for the following hypothesis. Active cholesterol inhibits cholesterol uptake and biosynthesis by suppressing both the expression and the activity of the gene products activated by SREBP-2; namely, HMGCR, LDLR and NPC1L1. It also reduces free cell cholesterol by serving as the substrate for its esterification by ACAT and for the synthesis of side-chain oxysterols, 27-hydroxycholesterol in particular. The oxysterols drive cholesterol depletion by promoting the destruction of HMGCR and stimulating sterol esterification as well as the activation of LXR. The latter fosters the expression of multiple homeostatic proteins, including four transporters for which active cholesterol is the likely substrate. By nulling active cholesterol, the manifold maintains the cellular sterol at its physiologic set point.

Brassica oilseed species are the third most important in the world, providing approximately 15 % of the total vegetable oils. Three species (Brassica rapa, B. juncea, B. napus) dominate with B. napus being the most common in Canada, China and Europe. Originally, B. napus was a crop producing seed with high erucic acid content, which still persists today, to some extent, and is used for industrial purposes. In contrast, cultivars which produce seed used for food and feed are low erucic acid cultivars which also have reduced glucosinolate content. Because of the limit to agricultural land, recent efforts have been made to increase productivity of oil crops, including Brassica oilseed species. In this article, we have detailed research in this regard. We have covered modern genetic, genomic and metabolic control analysis approaches to identifying potential targets for the manipulation of seed oil content. Details of work on the use of quantitative trait loci, genome-wide association and comparative functional genomics to highlight factors influencing seed oil accumulation are given and functional proteins which can affect this process are discussed. In summary, a wide variety of inputs are proving useful for the improvement of Brassica oilseed species, as major sources of global vegetable oil.

Peroxisome proliferator-activated receptors (PPARs) constitute a small family of three nuclear receptors that act as lipid sensors, and thereby regulate the transcription of genes having key roles in hepatic and whole-body energy homeostasis, and in other processes (e.g., inflammation), which have far-reaching health consequences. Peroxisome proliferator-activated receptor isotype α (PPARα) is expressed in oxidative tissues, particularly in the liver, carrying out critical functions during the adaptive fasting response. Advanced omics technologies have provided insight into the vast complexity of the regulation of PPAR expression and activity, as well as their downstream effects on the physiology of the liver and its associated metabolic organs. Here, we provide an overview of the gene regulatory networks controlled by PPARα in the liver in response to fasting. We discuss impacts on liver metabolism, the systemic repercussions and benefits of PPARα-regulated ketogenesis and production of fibroblast growth factor 21 (FGF21), a fasting- and stress-inducible metabolic hormone. We also highlight current challenges in using novel methods to further improve our knowledge of PPARα in health and disease.

Long-chain polyunsaturated fatty acids (LC-PUFA) like arachidonic acid (ARA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) constitute one-third to half of fish sperm lipids. Fish sperm is rich in phospholipid (PL)-primarily phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin. DHA is generally the most abundant LC-PUFA in each PL class, followed by competition between ARA and EPA. While the total n-6: n-3 PUFA ratio does not correlate significantly with sperm biomechanics, LC-PUFA do. DHA positively influences sperm biomechanics, while ARA and EPA may be negatively associated. Fish sperm maintains lower (≤1) total n-6 PUFA per unit of n-3 PUFA but keep a higher (>1) ARA per unit EPA. A weak dietary influence on sperm EPA and DHA exists but not on ARA. The DHA: EPA ratio in fish sperm is often >1, though values <1 occur. Certain species cannot fortify DHA sufficiently during spermatogenesis, diverging through whole genome duplications. Fish sperm can show ARA: EPA ratios greater or less than 1, due to shifts in prostaglandin pathways in different evolutionary eras. DHA-rich PL bilayers provide unique packing and fusogenic properties, with ARA/EPA-derived eicosanoids guiding sperm rheotaxis/chemotaxis, modulated by DHA-derived resolvins. Docosapentaenoic acid (DPA, 22:5n-3) sometimes substitutes for DHA in fish sperm.

Bacterial infections in humans and animals caused by multidrug-resistant (MDR) pathogens pose a serious threat to public health. New antibacterial targets are extremely urgent to solve the dilemma of cross-resistance. Phospholipids are critical components in bacterial envelopes and involve diverse crucial processes to maintain homeostasis and modulate metabolism. Targeting phospholipids and their synthesis pathways has been largely overlooked because conventional membrane-targeted substances are non-specific with cytotoxicity. In this review, we first introduce the structure and physiological function of phospholipids in bacteria. Subsequently, we describe the chemical diversity of novel ligands targeting phospholipids, structure-activity relationships (SAR), modes of action (MOA), and pharmacological effects. Finally, we prospect the advantage of bacterial phospholipids as promising antibacterial targets. In conclusion, these findings will shed light on discovering and developing new antibacterial drugs to combat MDR bacteria-associated infections.

High-grade serous ovarian cancer (HGSOC) represents the most lethal subtype of ovarian cancer, largely due to being commonly diagnosed at advanced stages. The early molecular mechanisms underlying ovarian carcinogenesis remain poorly defined, posing challenges to the development of prevention and early detection strategies. Here we dissect the molecular mechanisms of sex steroid hormone signaling throughout the decades-long evolution of HGSOC precursor lesions, which predominantly originate from secretory epithelial cells of fallopian tubes (FT). We also discuss the prognostic significance of sex steroid receptor isoforms and steroid metabolizing enzymes in HGSOCs. Finally, we provide a comprehensive gene expression atlases of sex steroid receptors, steroidogenic, and steroid-metabolizing enzymes across different cell populations in pre- and postmenopausal FTs, and HGSOCs, using published single-cell RNA sequencing datasets. These atlases reveal that secretory epithelial cells and stromal populations in FTs express sex steroid receptors and enzymes responsible for the formation and inactivation of genotoxic estrogen metabolites. In HGSOC, epithelial cells express various HSD17B isoforms and steroid conjugating enzymes, suggesting an enhanced ability to finely regulate the levels of bioactive sex steroids.

Polyunsaturated fatty acids (PUFAs) play numerous roles in living organisms but are also prone to rapid aerobic oxidation, resulting in the production of a wide range of isomeric metabolites called oxylipins. Among these, isoprostanes, discovered in the 1990s, are formed non-enzymatically from ω-3 and ω-6 PUFAs with 16 to 22 carbon atoms. Over nearly 35 years of research, two nomenclature systems for isoprostanes have been proposed and have evolved. However, as research progresses, certain aspects of the current nomenclature remain unclear and require further clarification to ensure precise identification of each metabolite and its corresponding parent PUFA. Therefore, we propose an update to the current nomenclature system, along with practical guidelines for assessing isoprostanoid diversity and identifying their PUFA origins.

In the human brain, palmitic acid (16:0; PAM) comprises nearly half of total brain saturates and has been identified as the third most abundant fatty acid overall. Brain PAM supports the structure of membrane phospholipids, provides energy, and regulates protein stability. Sources underlying the origin of brain PAM are both diet and endogenous synthesis via de novo lipogenesis (DNL), primarily from glucose. However, studies investigating the origin of brain PAM are limited to tracer studies utilizing labelled (C/C/H/H) PAM, and results vary based on the model and tracer used. Nevertheless, there is evidence PAM is synthesized locally in the brain, in addition to obtained directly from the diet. Herein, we provide an overview of brain PAM origin, entry to the brain, metabolic fate, and factors influencing brain PAM kinetics and levels, the latter in the context of age, as well as neurological diseases and psychiatric disorders. Additionally, we briefly summarize the role of PAM in signaling at the level of the brain. We add to the literature a rudimentary summary on brain PAM metabolism.

In 2016, the first worldwide n3 PUFA status map was published using the Omega-3 Index (O3I) as standard biomarker. The O3I is defined as the percentage of EPA + DHA in red blood cell (RBC) membrane FAs. The purpose of the present study was to update the 2016 map with new data. In order to be included, studies had to report O3I and/or blood EPA + DHA levels in metrics convertible into an estimated O3I, in samples drawn after 1999. To convert the non-RBC-based EPA + DHA metrics into RBC we used newly developed equations. Baseline data from clinical trials and observational studies were acceptable. A literature search identified 328 studies meeting inclusion criteria encompassing 342,864 subjects from 48 countries/regions. Weighted mean country O3I levels were categorized into very low ≤4%, low >4-6%, moderate >6-8%, and desirable >8%. We found that the O3I in most countries was low to very low. Notable differences between the current and 2016 map were 1) USA, Canada, Italy, Turkey, UK, Ireland and Greece (moving from the very low to low category); 2) France, Spain and New Zealand (low to moderate); and 3) Finland and Iceland (moderate to desirable). Countries such as Iran, Egypt, and India exhibited particularly poor O3I levels.

Terpenoids constitute one of the largest and most chemically diverse classes of primary and secondary metabolites in nature with an exceptional breadth of functional roles in plants. Biosynthesis of all terpenoids begins with the universal five‑carbon building blocks, isopentenyl diphosphate (IPP) and its allylic isomer dimethylallyl diphosphate (DMAPP), which in plants are derived from two compartmentally separated but metabolically crosstalking routes, the mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathways. Here, we review the current knowledge on the terpenoid precursor pathways and highlight the critical hidden constraints as well as multiple regulatory mechanisms that coordinate and homeostatically govern carbon flux through the terpenoid biosynthetic network in plants.

B cell malignancies, comprising over 80 heterogeneous blood cancers, pose significant prognostic challenges due to intricate oncogenic signaling. Emerging evidence emphasizes the pivotal role of disrupted lipid metabolism in the development of these malignancies. Variations in lipid species, such as phospholipids, cholesterol, sphingolipids, and fatty acids, are widespread across B cell malignancies, contributing to uncontrolled cell proliferation and survival. Phospholipids play a crucial role in initial signaling cascades leading to B cell activation and malignant transformation through constitutive B cell receptor (BCR) signaling. Dysregulated cholesterol and sphingolipid homeostasis support lipid raft integrity, crucial for propagating oncogenic signals. Sphingolipids impact malignant B cell stemness, proliferation, and survival, while glycosphingolipids in lipid rafts modulate BCR activation. Additionally, cancer cells enhance fatty acid-related processes to meet heightened metabolic demands. In obese individuals, the obesity-derived lipids and adipokines surrounding adipocytes rewire lipid metabolism in malignant B cells, evading cytotoxic therapies. Genetic drivers such as MYC translocations also intrinsically alter lipid metabolism in malignant B cells. In summary, intrinsic and extrinsic factors converge to reprogram lipid metabolism, fostering aggressive phenotypes in B cell malignancies. Therefore, targeting altered lipid metabolism has translational potential for improving risk stratification and clinical management of diverse B cell malignancy subtypes.

Plants and algae play a crucial role in the earth's ecosystems. Through photosynthesis they convert light energy into chemical energy, capture CO2 and produce oxygen and energy-rich organic compounds. Photosynthetic organisms are primary producers and synthesize the essential omega 3 and omega 6 fatty acids. They have also unique and highly diverse complex lipids, such as glycolipids, phospholipids, triglycerides, sphingolipids and phytosterols, with nutritional and health benefits. Plant and algal lipids are useful in food, feed, nutraceutical, cosmeceutical and pharmaceutical industries but also for green chemistry and bioenergy. The analysis of plant and algal lipidomes represents a significant challenge due to the intricate and diverse nature of their composition, as well as their plasticity under changing environmental conditions. Optimization of analytical tools is crucial for an in-depth exploration of the lipidome of plants and algae. This review highlights how lipidomics analytical tools can be used to establish a complete mapping of plant and algal lipidomes. Acquiring this knowledge will pave the way for the use of plants and algae as sources of tailored lipids for both industrial and environmental applications. This aligns with the main challenges for society, upholding the natural resources of our planet and respecting their limits.

Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.

Oxylipins are potent lipid mediators with increasing interest in clinical research. They are usually measured in systemic circulation and can provide a wealth of information regarding key biological processes such as inflammation, vascular tone, or blood coagulation. Although procedures still require harmonization to generate comparable oxylipin datasets, performing comprehensive profiling of circulating oxylipins in large studies is feasible and no longer restricted by technical barriers. However, it is essential to improve and facilitate the biological interpretation of complex oxylipin profiles to truly leverage their potential in clinical research. This requires regular updating of our knowledge about the metabolism and the mode of action of oxylipins, and consideration of all factors that may influence circulating oxylipin profiles independently of the studied disease or condition. This review aims to provide the readers with updated and necessary information regarding oxylipin metabolism, their different forms in systemic circulation, the current limitations in deducing oxylipin cellular effects from in vitro bioactivity studies, the biological and technical confounding factors needed to consider for a proper interpretation of oxylipin profiles.

Atherosclerosis is a causative factor associated with cardiovascular disease (CVD). Over the past few decades, extensive research has been carried out on the relationship between the n-6/n-3 fatty acid ratio of ingested lipids and the progression of atherosclerosis. However, there are still many uncertainties regarding the precise nature of this relationship, which has led to challenges in providing sound dietary advice to the general public. There is therefore a pressing need to review our current understanding of the relationship between the dietary n-6/n-3 fatty acid ratio and atherosclerosis, and to summarize the underlying factors contributing to the current uncertainties. Initially, this article reviews the association between the n-6/n-3 fatty acid ratio and CVDs in different countries. A summary of the current understanding of the molecular mechanisms of n-6/n-3 fatty acid ratio on atherosclerosis is then given, including inflammatory responses, lipid metabolism, low-density lipoprotein cholesterol oxidation, and vascular function. Possible reasons behind the current controversies on the relationship between the n-6/n-3 fatty acid ratio and atherosclerosis are then provided, including the precise molecular structures of the fatty acids, diet-gene interactions, the role of fat-soluble phytochemicals, and the impact of other nutritional factors. An important objective of this article is to highlight areas where further research is needed to clarify the role of n-6/n-3 fatty acid ratio on atherosclerosis.

One of the major constituents of mitochondrial membranes is the phospholipids, which play a key role in maintaining the structure and the functions of the mitochondria. However, mitochondria do not synthesize most of the phospholipids in situ, necessitating the presence of phospholipid import pathways. Even for the phospholipids, which are synthesized within the inner mitochondrial membrane (IMM), the phospholipid precursors must be imported from outside the mitochondria. Therefore, the mitochondria heavily rely on the phospholipid transport pathways for its proper functioning. Since, mitochondria are not part of a vesicular trafficking network, the molecular mechanisms of how mitochondria receive its phospholipids remain a relevant question. One of the major ways that hydrophobic phospholipids can cross the aqueous barrier of inter or intraorganellar spaces is by apposing membranes, thereby decreasing the distance of transport, or by being sequestered by lipid transport proteins (LTPs). Therefore, with the discovery of LTPs and membrane contact sites (MCSs), we are beginning to understand the molecular mechanisms of phospholipid transport pathways in the mitochondria. In this review, we will present a brief overview of the recent findings on the molecular architecture and the importance of the MCSs, both the intraorganellar and interorganellar contact sites, in facilitating the mitochondrial phospholipid transport. In addition, we will also discuss the role of LTPs for trafficking phospholipids through the intermembrane space (IMS) of the mitochondria. Mechanistic insights into different phospholipid transport pathways of mitochondria could be exploited to vary the composition of membrane phospholipids and gain a better understanding of their precise role in membrane homeostasis and mitochondrial bioenergetics.

Lipid oxidation constitutes the main source of degradation of lipid-rich foods, including food emulsions. The complexity of the reactions at play combined with the increased demand from consumers for less processed and more natural foods result in additional challenges in controlling this phenomenon. This review provides an overview of the insights acquired over the past two decades on the understanding of lipid oxidation in oil-in-water (O/W) emulsions. After introducing the general structure of O/W emulsions and the classical mechanisms of lipid oxidation, the contribution of less studied oxidation products and the spatiotemporal resolution of these reactions will be discussed. We then highlight the impact of emulsion formulation on the mechanisms, taking into consideration the new trends in terms of emulsifiers as well as their own sensitivity to oxidation. Finally, novel antioxidant strategies that have emerged to meet the recent consumer's demand will be detailed. In an era defined by the pursuit of healthier, more natural, and sustainable food choices, a comprehensive understanding of lipid oxidation in emulsions is not only an academic quest, but also a crucial step towards meeting the evolving expectations of consumers and ensuring the quality and stability of lipid-rich food products.

The outermost epidermal layer of the skin, the stratum corneum, is not simply a barrier that safeguards skin integrity from external insults and invaders, it is also a delicately integrated interface composed of firm, essentially dead corneocytes and a distinctive lipid matrix. Together, the stratum corneum lipid matrix and sebum lipids derived from sebaceous glands give rise to a remarkably complex but quite unique blend of skin surface lipids that demonstrates tremendous heterogeneity and provides the skin with its indispensable protective coating. The stratum corneum lipid matrix is composed primarily of three major lipid classes: ceramides, non-esterified fatty acids and cholesterol, whereas sebum is a waxy mixture predominantly composed of acylglycerols, wax esters, non-esterified fatty acids, squalene, cholesterol and cholesterol esters. The balance of these skin surface lipids in terms of their relative abundance, composition, molecular organisation and dynamics, and their intricate interactions play a crucial role in the maintenance of healthy skin. For that reason, even minuscule alterations in skin surface lipid properties or overall lipid profile have been implicated in the aetiology of many common skin diseases including atopic dermatitis, psoriasis, xerosis, ichthyosis and acne. Novel lipid-based interventions aimed at correcting the skin surface lipid abnormalities have the potential to repair skin barrier integrity and the symptoms associated with such skin diseases, even though the exact mechanisms of lipid restoration remain elusive.

Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders.

Phosphatidylglycerol (PG) is a unique phospholipid class with its indispensable role in photosynthesis and growth in land plants, algae, and cyanobacteria. PG is the only major phospholipid in the thylakoid membrane of cyanobacteria and plant chloroplasts and a main lipid component in photosynthetic protein-cofactor complexes such as photosystem I and photosystem II. In plants and algae, PG is also essential as a substrate for the biosynthesis of cardiolipin, which is a unique lipid present only in mitochondrial membranes and crucial for the functions of mitochondria. PG biosynthesis pathways in plants include three membranous organelles, plastids, mitochondria, and the endoplasmic reticulum in a complex manner. While the molecular biology underlying the role of PG in photosynthetic functions is well established, many enzymes responsible for the PG biosynthesis are only recently cloned and functionally characterized in the model plant species including Arabidopsis thaliana and Chlamydomonas reinhardtii and cyanobacteria such as Synechocystis sp. PCC 6803. The characterization of those enzymes helps understand not only the metabolic flow for PG production but also the crosstalk of biosynthesis pathways between PG and other lipids. This review aims to summarize recent advances in the understanding of the PG biosynthesis pathway and functions of involved enzymes.

Membrane lipidomes are dynamic and their changes generate lipid mediators affecting various biological processes. Phosphatidic acid (PA) has emerged as an important class of lipid mediators involved in a wide range of cellular and physiological responses in plants, animals, and microbes. The regulatory functions of PA have been studied primarily outside the nuclei, but an increasing number of recent studies indicates that some of the PA effects result from its action in nuclei. PA levels in nuclei are dynamic in response to stimuli. Changes in nuclear PA levels can result from activities of enzymes associated with nuclei and/or from movements of PA generated extranuclearly. PA has also been found to interact with proteins involved in nuclear functions, such as transcription factors and proteins undergoing nuclear translocation in response to stimuli. The nuclear action of PA affects various aspects of plant growth, development, and response to stress and environmental changes.