The endocannabinoidome (eCBome) is a complex lipid signaling network that integrates metabolic, immune, and neurobehavioral processes in response to environmental cues. Dietary lipids and gut microbiota have emerged as major modulators of its activity and signaling tone. Intake of specific fatty acids, including the monounsaturated oleic acid, the omega-6 polyunsaturated linoleic acid, and omega-3 polyunsaturated fatty acids, influences the eCBome not only by serving as structural precursors of bioactive lipid mediators, but also by altering the relative abundance of these mediators through changes in substrate availability, enzymatic competition, and receptor-mediated feedback loops. Concurrently, gut microbiota shape host eCBome signaling by regulating lipid metabolism, inflammatory tone, and intestinal barrier integrity, while eCBome mediators reciprocally modulate microbial composition and function. Dysregulation of this complex diet-microbiota-eCBome interplay has been implicated in the pathogenesis of metabolic disorders, chronic inflammation, and neuropsychiatric conditions. In this review, we critically examine the molecular mechanisms underlying the interactions between dietary lipid composition, gut microbial ecology, and eCBome signaling. We discuss the implications for human health and highlight emerging diet-based therapeutic strategies targeting this axis.
Cardiometabolic diseases (CMD) are a major global health threat. Given their multifactorial pathogenesis, understanding the interconnected mechanisms driving disease progression is essential. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron accumulation, lipid peroxidation, and compromised antioxidant defenses, is emerging as a promising target for therapeutic intervention in CMD. Growing evidence underscores the intricate interplay among iron metabolism, redox homeostasis, and lipid metabolism in regulating ferroptosis and CMD. Notably, we propose the concept of an "iron paradox" as an integrative framework to synthesize these observations. Despite representing opposite systemic iron states, both iron deficiency and iron overload can converge on ferroptotic vulnerability by disrupting subcellular iron trafficking, mitochondrial function, lipid remodeling, and antioxidant defense. This framework emphasizes that ferroptosis risk in CMD is not primarily governed directly by absolute iron abundance, but more so the interaction between redox-active iron, PUFA-containing phospholipids and lipid peroxide detoxification systems. We then describe the molecular regulation of ferroptosis, with a focus on disruptions in iron and lipid homeostasis as drivers of lipid peroxidation. The contribution of these cellular changes to CMD pathophysiology is then described. Finally, we summarize preclinical evidence supporting ferroptosis-targeted interventions and outline future directions for translational research and therapeutic innovation.
The oxidation of cholesterol at the Δ5 double bond generates 5,6-epoxycholestanols (5,6-ECs), which exist as two diastereoisomers, 5,6α-EC and 5,6β-EC. These metabolites define a distinct branch of sterol metabolism that integrates redox chemistry with receptor signaling. Once considered artefactual autoxidation products, 5,6-ECs are now recognized as regulated intermediates arising from enzymatic, oxidative, and environmental sources, and yielding structurally and functionally diverse metabolites, here termed the epoxycholestanoid (EChA) family. Cholesterol-5,6-epoxide hydrolase (ChEH; EBP/DHCR7 complex) converts 5,6-ECs into cholestane-3β,5α,6β-triol (CT), which is subsequently oxidized by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) to form 6-oxocholestan-3β,5α-diol (OCDO), a glucocorticoid receptor (GR)-biased agonist that promotes tumor growth. In parallel, 5,6α-EC undergoes stereoselective conjugation with histamine to generate dendrogenin A (DDA), an endogenous liver X receptor β (LXRβ)-biased agonist that displays tumor suppressive and neurostimulating functions. These opposing OCDO-GR and DDA-LXRβ pathways are embedded in enzyme-coupled feedback loops that link oxidative stress, sterol metabolism, and transcriptional control. This review integrates lipidomics, enzymology, receptor pharmacology, and disease biology to define the EChA family as a conserved redox-responsive signaling network at the interface of cholesterol metabolism, inflammation, ageing, and disease, offering new opportunities for biomarker discovery and therapeutic intervention.
Oxysterols and bile acids, historically viewed as cholesterol byproducts, are now a center of research interest for their roles in physiological and pathological processes. Here we explore the complexities of oxysterol metabolism and bile acid biosynthesis, highlighting the intricate interplay of enzymes in the oxysterome and the network of intermediates in bile acid synthesis. The biological importance of these compounds has led to the development of methods for quantifying them. As discussed here, while these methods provide useful information for biological studies, future methods for the combined analysis of oxysterols and bile acids would further accelerate research in the field, and enable a better understanding of bile acid pathways and the associated diseases. This review provides an overview of the current understanding of oxysterol metabolism and bile acid biosynthesis, highlighting metabolic pathways, analytical challenges, and their relevance to inherited disorders of bile acid metabolism.
Throughout development and in response to fluctuating environmental conditions, plants rely on autophagy to degrade and recycle cytoplasmic material thereby maintaining cellular homeostasis. This pathway is characterized by the de novo formation of double-membrane vesicles, the autophagosomes, that selectively sequester and deliver cargo to the vacuole for degradation. The biogenesis of these specialized structures is driven by intense membrane remodelling events of which both lipid quantity and quality are emerging key actors. Recent advances have unraveled the singular lipid composition of autophagic membranes, provided mechanistic insights into the functions of membrane lipids during autophagy and highlighted critical determinants of lipid transport for membrane expansion during autophagosome formation. In this review, we synthesize current knowledge on the nature, functions and trafficking of membrane lipids during autophagy with a particular focus on the model plant Arabidopsis thaliana. We further discuss outstanding questions regarding lipids dynamics and lipid-protein cooperation in autophagic membranes and compare lipid-related mechanisms in plants to that of other organisms. Together, these advances expand the conceptual framework of autophagy and underscore lipids as key regulators of plant acclimation and survival.
Plants in their natural habitats encounter abiotic and biotic stress factors, making sensing and responding to stresses integral components of their lifestyle. The ability to respond to environmental cues is essential for plant fitness, and thus, plants have evolved molecular mechanisms to cope with these challenges. This review updates recent advances in understanding how plasma membrane (PM) biology contributes to plant responses against biotic stresses. Emphasis is placed on the dynamic roles of membrane lipids, which play crucial roles in defining protein composition and function of the PM at the plant-pathogen interface. Emerging insights into PM nanostructure and lipid-mediated signaling reveal how rapid, dynamic and localized lipid remodeling supports effective defense activation during pathogen attack. Evidence from various plant models suggests that multi-layered regulatory mechanisms control the lipid composition of the PM, enabling plants to manage intrinsic PM properties and hence, processes that minimize the susceptibility to pathogen exploitation. From the pathogens' perspective, successful infection requires subverting plant defenses and manipulating host PM function for colonization. A deeper understanding of plant PM dynamics during pathogen challenge will provide knowledge for crop improvement strategies, opening novel avenues to enhance resistance at the frontline of plant-pathogen interactions.
Vitamin A deficiency remains a major health issue in many countries. Two types of vitamin A are naturally present in our diet, provitamin A carotenoids from plant sources and preformed vitamin A, mainly retinyl esters and retinol, found in animal products, fortified foods and supplements. The objective was to review current knowledge and gaps in understanding the mechanism and factors influencing preformed vitamin A bioavailability. The results show that the fate of retinyl esters in the intestine is well described, but that of retinol deserves further investigation. Preformed vitamin A present in liver, oil, sugar, and milk is well absorbed (70 to 99%), but data for other important matrices like eggs and fortified flours is lacking. The impact of the type and quantity of dietary lipids is unclear, especially whether low levels in a meal would be sufficient for optimal vitamin A absorption. Further research is needed to evaluate the effect of plant proteins and dietary fibers for which results are conflicting. The impact of host related factors like age is limited, and largely unknown for gender and genetic/epigenetic factors. It is well established that inflammation and other metabolic disorders affect vitamin A status, yet further study could help to distinguish absorption issues from other metabolic processes. An interesting avenue is the possible role of microbiota and probiotics on vitamin A absorption, as it could represent a complementary approach to food fortification. Further clinical research should prioritize the use of tracers to better quantify absorption under various nutritional conditions.
Oxylipins are bioactive lipid mediators derived from the enzymatic and non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs). They play diverse and potent roles in biological processes, with increasing relevance to a wide range of diseases and dietary interventions. While significant advances have been made in oxylipin profiling using targeted mass spectrometry-based techniques, challenges remain in the interpretation, integration, and visualization of these complex datasets. This review critically evaluates current methodologies, highlighting the application of classical statistical tests, regression models, and multivariate statistical methods (MSMs). MSMs, such as principal component analysis, partial least squares discriminant analysis, and non-metric multidimensional scaling, offer key advantages for exploring high-dimensional, collinear oxylipin datasets and are well-suited for both cross-sectional and time-course study designs. Newer approaches, including machine learning and deep learning models, are emerging as powerful tools but are currently constrained by data availability. We also review the integration of oxylipins into multi-omics frameworks and pathway-based analyses, highlighting opportunities and limitations in bioinformatics infrastructure. Finally, we propose future directions to enhance the biological interpretability of oxylipin data through pathway enrichment tools and incorporation into established omics platforms. Together, these developments will strengthen the understanding of oxylipin roles in systems biology and translational lipid research.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent liver disorder deriving from the chronic exposure to hepatocyte steatosis and its lipotoxicity effects, as mitochondrial dysfunction, overactivation of stress response and inflammatory genes, and cell death signaling. Genomics and post-genomic disciplines are now offering unprecedent opportunities in disease mechanisms characterization, precision diagnostics, and treatment. These disciplines include nutrigenomics, i.e. the use of genomics techniques to study the health effects of the interaction between diet/nutrients and the genome. Its applications can be particularly useful to study lifestyle and dietary modifications, and to assess the efficacy of nutritional interventions through the criteria of precision medicine. Specific examples include interventions with fat-soluble vitamins and other lipid nutrients as omega-3 fatty acids, which have shown cytoprotective properties and molecular effects useful in modulating key steps of the hepatocellular lipotoxicity process, such as lipid biosynthesis, lipid peroxidation inflammatory gene activation and cell death signaling. Other applications of nutrigenomics concern drug discovery and preclinical studies to explore therapeutic mechanisms, efficacy and safety of new vitamin products and nutraceuticals. This review discusses current evidence on hepatocyte lipotoxicity and its nutrigenomic exploration to identify disease mechanisms, nutritional defects and intervention strategies with these lipid nutrients. Their properties, limitations, and potential for translation in the prevention and clinical management of MASLD are critically evaluated.
Preterm birth has a worldwide prevalence of around 11 %, and > 95 % of preterm infants now survive into adulthood. However, improved survival is accompanied by increased risks of later life chronic disorders. The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), which are essential for optimum brain and visual system development, and cardiovascular and immune system function. Fetal demand for ARA and DHA is high, especially in the last trimester. Prior to birth they are provided by placental transfer, enriched by placental biomagnification, which occurs in parallel with placental bioreduction of linoleic acid (LA). However, after birth preterm infant feeding results in marked decreases in tissue levels of ARA and DHA, and concomitant increases in LA. This phenomenon we term the Preterm PUFA Gap, which may be a key factor in adverse health consequences of preterm birth. The review begins with a summary of the evidence highlighting the importance of DHA in reducing the risk of early preterm birth. We then develop the concept of the Preterm PUFA Gap, including discussion of the conflicting results of intervention trials with ARA and DHA. This is followed by a review of potential approaches to close the Preterm PUFA Gap.
In the last few years, fatty acids have gained increasing recognition as key modulators of neurodegenerative disease onset and progression. As the fundamental building blocks of most lipids, they not only maintain membrane structure but also support diverse cellular functions. In this review, we summarize their biochemical structures and major classifications, and we describe the pathways governing their synthesis, uptake, and trafficking in the brain. We further explore how fatty acids influence electrophysiological processes by modulating membrane channel conductance, ion-channel-gating, and receptor-mediated signaling, thereby impacting synaptic transmission and cognition performance. Finally, we examine evidence linking fatty acid dynamics in neurodegenerative pathophysiology, highlighting their dual role as both protective and detrimental agents in brain health.
Phospholipids are essential components of cellular membranes in plants and play important roles in several biological processes including membrane biogenesis, signaling, and stress response. Here, we systematically review the metabolic pathways that coordinate the assembly and degradation of phospholipids, as well as the functional roles of phospholipids in plant growth. To achieve this, we summarize recent biochemical and physiological studies of key enzymes involved in these pathways, and highlight the regulation of phospholipid metabolism at the transcriptional, post-transcriptional, and post-translational levels. These processes facilitate dynamic adjustments in phospholipid levels in response to environmental stressors and signaling pathways, and are crucial for maintaining phospholipid homeostasis and plant development. In addition, beyond their roles in maintaining the structural integrity of biological membranes, we also discuss crosstalk between phospholipid metabolic pathways, glycolipid production, and lipid droplet formation. Collectively, these insights contribute to a deeper understanding of phospholipid dynamics and their multifunctional roles in plants.
Diacylglycerol (DAG) and phosphatidic acid (PA), being positioned in the central hub of glycerophospholipid biosynthesis pathways, are lipids vital for the structural and functional integrity of the cell. DAG kinases (DGKs) are the enzymes responsible for the conversion of DAG to PA to regulate the dynamically changing spatiotemporal levels of these lipids in various organelles and cellular structures. DAG and PA thereby function intricately in mechanistic events like cell signaling in association with the intracellular lipid profiles controlling membrane physiology. In mammalian cells, there are ten DGK isoforms, i.e., α, β, γ, δ, η, κ, ε, ζ, ι, θ, and their splice variants. Recent advancement of structural prediction algorism enables us to gain unparalleled insights into their molecular architectures, despite limited experimental data available to date. The structural information gives fundamental clues to understand pertinent cellular events that are reviewed in this work on a broad range of topics in health and disease. Upon cell stimuli, DAG is formed by hydrolysis of a phospholipid such as phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P2) via a phospholipase C (PLC). While relationship of the DGK activity with specific lipid acyl-chain species is being recognized, that with the sn-1 ether linkage like the vinyl ether has not yet been revealed. Importance of these relationships may be evident, considering the known regulation of the PLC activity by lipid rafts. Elucidation of molecular details of DGK functions in the context of membrane biophysics is thus essential for our understanding of cellular events in the individual tissues and organs.
Lipoprotein (a) [Lp(a)] is a highly heterogeneous lipoprotein particle promoting panvascular disease. Structurally, it consists of an LDL-like core covalently bound to apolipoprotein (a) [apo(a)]. Molecular determinants linking various genetic variants of apo(a) constituent of Lp(a) to vascular pathology remain incompletely defined. We have built a model allowing dissection which variations in LPA gene are functional, and which are mere associates of these functional variations. Copy number changes in kringle IV type 2 (KIV-2), together with a spectrum of single nucleotide polymorphisms (SNPs), regulate apo(a) size, expression, and function. These variants can be broadly categorized into Lp(a)-increasing, Lp(a)-lowering, and null alleles, with distinct prevalence across populations. Notably, risk alleles such as rs10455872 and rs3798220 account for substantial variance in circulating Lp(a) and confer elevated susceptibility to coronary artery disease, whereas splice-altering and nonsense alleles markedly reduce Lp(a) concentrations. The therapeutic implications of modifying circulating Lp(a) levels are profound. While conventional lipid-lowering therapies exert little influence on Lp(a), antisense oligonucleotides (pelacarsen) and small interfering RNA agents (olpasiran, SLN360) achieve robust Lp(a) reductions. Integrating genetic insights with structural modeling provides a framework to disentangle functional from proxy associations within LPA and neutralize the cardiovascular hazard conferred by elevated levels of Lp(a).
The conversion of straight chain saturated fatty acids to their bent, unsaturated counterparts significantly increases their structural and functional complexity. Desaturation of fatty acids, where double bonds are introduced is an enzymatic reaction. Exploring 56 eukaryotic genomes, 275 desaturase homologs have been identified. Membrane-bound desaturases are the dominant form and are ubiquitous in bacteria and eukaryotes. Four subfamilies of desaturases introduce double bonds at distinct locations. Among them, the First Desaturase subfamily introduces the first double bond among which the stearoyl-CoA desaturases (SCDs) are the most predominant. SCD is a rate-limiting enzyme that generates monounsaturated fatty acids (MUFA) from saturated fatty acids (SFA) at the endoplasmic reticulum membrane, where SCD is localized. The MUFAs are utilized to produce a variety of cell membrane components including triglycerides, phospholipids, and cholesterol esters which play important roles in membrane fluidity, organelle function, and signal transduction. SCD activity is a critical regulator of SFA to MUFA ratio and, therefore, of overall cell function, growth, and survival. In this review, we will provide the latest updates on the expected as well as unanticipated roles of SCD in development, metabolism and disease with a focus on cancer and the central nervous system.
Membrane contact sites (MCSs) are fundamental hubs of inter-organelle communication that mediate the non-vesicular exchange of lipids, ions, and metabolites, thereby sustaining cellular homeostasis. In plants, the "contactome"-the dynamic network of all membrane contact sites-has evolved distinctive features to accommodate the requirements of a sessile, photosynthetic lifestyle and the presence of plastids. Within this network, the endoplasmic reticulum (ER) functions as a central hub for lipid biosynthesis and distribution, forming functionally important contacts with multiple organelles. Recent advances in high-resolution imaging, lipidomics, and molecular genetics are beginning to uncover the complexity of these inter-organelle connections and their contribution to lipid homeostasis in plants. This review summarizes current knowledge of the plant contactome, with a focus on lipid transfer proteins and lipid-modifying enzymes that maintain lipid balance during organelle biogenesis, plant development, and stress adaptation. Plant lipid transfer at membrane contact sites can be broadly divided into two mechanistic modes: precision-regulated "shuttles," exemplified by the Ca2+-dependent SYT1-mediated diacylglycerol transfer at ER-plasma membrane interfaces, and high-capacity lipid transfer mechanisms, such those mediated by ATG2, that support rapid lipid flux during autophagosome biogenesis. Knowledge of lipid metabolism at plant membrane contact sites is still in its initial stages, and many of the underlying mechanisms remain unexplored. Major challenges include understanding how these sites integrate stress responses, metabolic fluxes, and organelle dynamics. Addressing these questions will be essential to unravel the unique aspects of plant lipid biology and may open opportunities for improving stress resilience and metabolic engineering in crops.
Myristic acid (14:0) is a relatively minor fatty acid in terms of abundance yet, in certain biological settings, it has a major impact. Although normally synthesized via the classical fatty acid biosynthesis pathway, in specific cases where larger quantities of myristate are required, animals express distinct thioesterase enzymes that hydrolyze the acyl-S-fatty acid synthase thioester bond prior to further chain elongation. In the parasitic kinetoplastid, Trypanosoma brucei, myristate is required for biosynthesis of dimyristoyl-glycosylphosphatidylinositol membrane anchors, to which variable surface glycoproteins are attached. This extracellular coat protein is changed periodically, allowing the parasite to evade host adaptive immunity. In protein N-myristoylation, this acyl chain is attached to N-terminal glycine residues via an amide bond. A search for inhibitors of N-myristoyltransferase (NMT) activity led to discovery of pyrazole sulfonamide compounds with potent T. brucei NMT inhibitory activity. While clinical development of these inhibitors for parasite-induced disease has not been realized, the observation that pyrazole sulfonamides possess anticancer activity led to drug development studies. Findings obtained with a specific pyrazole sulfonamide compound, branded as zelenirstat, have yielded promising results in cell culture studies, animal models and human clinical trials. This review describes research undertaken to validate zelenirstat as a cancer therapy option.
Plant oils, primarily composed of triacylglycerols (TAGs), are essential for both food and industrial applications. TAGs consist of three fatty acids esterified to a glycerol backbone, and their value and functionality are largely determined by their fatty acid composition. Hence, enhancing the fatty acid profile of plant oils is a primary focus for improving their economic and practical potential. Phosphatidylcholine: Diacylglycerol Cholinephosphotransferase (PDCT), encoded by the REDUCED OLEATE DESATURATION1 (ROD1) gene in Arabidopsis thaliana, catalyzes the interconversion between phosphatidylcholine, the site of fatty acid modification, and diacylglycerol, the precursor of TAG assembly. PDCT plays a key role in determining the fatty acid composition and quality of oils, making it an attractive target for engineering crops with tailored oil profiles. This review systematically examines the biochemical, genetic, and molecular biology research on PDCT over the past decades, focusing on its phylogeny, physiological roles, regulation, biochemical characterization, structural features, and biotechnological applications. We also analyze the predicted structure of PDCT, which suggests a domain-swapped homodimer configuration based on AlphaFold3 modeling, and we discuss potential catalytic mechanisms. Finally, we highlight key open questions in the field and propose future research directions.
