Search Results (163)

Palmitic acid (PA), the most abundant saturated fatty acid in the human body, is implicated in lipotoxicity under hyperlipidemic conditions, with potential consequences for bone metabolism. To investigate its impact on developing bone tissue, this study used an ex vivo organotypic embryonic chick femur model, exposing femora to control (0 µM), low (50 µM), and high (200 µM) PA concentrations. A multimodal approach, integrating microtomographic, histochemical, ultrastructural, and gene expression analyses, was used to assess tissue architecture, matrix composition, mineralization, and molecular adaptations. PA exposure significantly reduced longitudinal femoral growth, as evidenced by decreased femoral length and tissue volume. Gene expression analysis revealed reduced expression of selected osteogenic differentiation-related markers, including RUNX2, BMP2, and SPP1. However, COL1A2 expression was upregulated, correlating with increased collagenous matrix deposition and enhanced mineralization in PA-treated groups. Alcian blue staining further suggested reduced proteoglycan-rich cartilage matrix, particularly at 200 µM PA. Additionally, PA modulated the expression of both pro-inflammatory and anti-inflammatory mediators, along with increased autophagy-associated responses, as suggested by the upregulation of autophagy-related genes and the presence of autophagosomes and autolysosomes. These findings indicate that PA does not simply exert a deleterious effect on bone tissue but rather redirects the developmental trajectory of the organotypic femur by reducing longitudinal growth while promoting collagen-rich matrix maturation and mineral compaction. This response may involve altered cartilage-associated endochondral processes, fatty-acid-driven metabolic adaptation, osteoblast/osteocyte maturation, and autophagy-associated matrix processing under lipid-enriched conditions. Full article

Clutch persistence, defined as the ability to sustain consecutive egg-laying cycles, is a pivotal determinant of profitability in the poultry industry, particularly for aging laying hens (≥65 weeks). However, the molecular mechanisms governing this trait remain elusive, largely due to the traditional “ovary-centric” paradigm that overlooks systemic regulation by the gut microbiota. To address this knowledge gap, the present study aimed to dissect the comprehensive regulatory network governing clutch persistence using integrated multi-omics analyses. A total of 20 sixty-five-week-old Rhode Island Red (RIR) laying hens with cumulative egg production exceeding 300 eggs but distinct clutch persistence were stratified into a high-clutch persistence group (HCP, ≥25 clutches, n = 10) and a low-clutch persistence group (LCPLCP, ≤15 clutches, n = 10). Multi-omics profiling, including ovarian transcriptomics, proteomics, and metabolomics; serum metabolomics; and cecal microbiota 16S rRNA sequencing was performed. Data integration and association mining were conducted via Spearman correlation analysis with stringent thresholds (r > 0.6, p < 0.01). Integrated analyses revealed a “gut–ovary axis” regulatory model mediated by a lipid mediator network, operating through a three-tiered mechanism: (1) Gut Initiation: The HCP group exhibited enriched cecal γ-Proteobacteria, which promoted biosynthesis of lipid precursors. (2) Serum Transport: Key serum lipid mediators, most notably LysoPC (22:6) (VIP = 4.5) and cholesterol ester CE (20:4), served as critical carriers transducing gut-derived signals to the ovary. (3) Ovarian Execution: These lipid signals activated a core ovarian metabolic pathway centered on the PLA2G6-ALOX15B-AGPAT3 axis, which coordinated follicular development and ovulation by supplying steroid hormone synthesis substrates, exerting anti-inflammatory effects, and stabilizing membrane structures. Collectively, this study demonstrates that gut microbiota modulates clutch persistence in aging laying hens via lipid mediators, orchestrating a systemic “gut–serum–ovary” regulatory cascade. These findings provide a novel molecular framework for extending the economic egg-laying cycle through the targeted manipulation of intestinal microbiota or serum lipid metabolism. Full article

Phospholipid fatty acid incorporation and remodeling are central processes through which immune cells adapt their membranes during activation. Macrophages are known to integrate oxidized fatty acids into phospholipids, yet the principles governing this distribution remain incompletely defined. Hydroxyeicosatetraenoic acids (HETEs) are abundant products generated during inflammation, and their integration into membrane phospholipids may influence signaling, trafficking, and membrane organization. Although individual HETE isomers differ in biosynthesis and function, it is not known whether macrophages handle them differently. Here, we address how 5-, 12-, and 15-HETE are incorporated into murine peritoneal macrophage phospholipids during inflammatory stimulation. We show that each isomer exhibits a distinctive phospholipid-class distribution, with 12-HETE preferentially entering choline phospholipids (PC), 15-HETE enriching phosphatidylinositol (PI), and 5-HETE distributing more broadly across PC, PI and ethanolamine phospholipids (PE). All three isomers are incorporated predominantly at the sn-2 position and showed similar molecular species distribution within each class, with diacyl PC, PE plasmalogens, and PI(18:0/HETE) serving as dominant acceptors. RAW264.7 cells reproduce these patterns. In ether phospholipid-deficient RAW.108 cells, incorporation into ether species is lost but compensated by increased routing into diacyl PC and PE, while PI incorporation remains unchanged. Collectively, these findings reveal that phospholipid class, not simple availability, determines where HETEs are incorporated. This distribution is preserved across macrophage cell types and remains intact even when ether phospholipids are absent, indicating that class specific pathways, rather than lipid subclass composition, primarily determine HETE incorporation. Full article

For decades, the pharmacological identity of Panax ginseng has been primarily attributed to triterpenoid saponins known as ginsenosides. However, accumulating evidence indicates that ginseng also contains a structurally distinct lipid–protein complex, termed gintonin, enriched in lysophosphatidic acid (LPA) species. Unlike ginsenosides, which predominantly exert modulatory effects on membrane dynamics and intracellular kinase pathways, gintonin directly activates LPA G protein-coupled receptors (GPCRs), thereby inducing rapid phospholipase C (PLC) activation and intracellular Ca²⁺ mobilization. Biochemical analyses have identified major LPA species within the gintonin fraction, including C16:0, C18:0, and C18:1, stabilized within a proteinaceous matrix that may influence receptor engagement kinetics. Pharmacological studies demonstrate that gintonin preferentially activates LPA₁ and LPA₃ receptor subtypes, triggering downstream signaling cascades involving MAPK, PI3K/Akt, and Rho pathways. These receptor-mediated effects occur on a rapid temporal scale, distinguishing gintonin from the slower transcriptional and kinase-modulating actions of ginsenosides. In this review, we synthesize current evidence regarding the chemical architecture, receptor pharmacology, and signaling dynamics of gintonin and propose a dual signaling framework in which steroid-like saponins and lipid GPCR ligands represent complementary molecular axes within P. ginseng. Recognition of this layered signaling organization refines the molecular understanding of ginseng biology and highlights gintonin as a unique plant-derived GPCR ligand system. Full article

ATP-binding cassette A1 (ABCA1) is a critical molecule in facilitating cholesterol transport in a variety of organs. In the nervous system, cholesterol supply is essential and rate-limiting for myelin biogenesis, which underlies efficient conduction of nerve impulses. When myelin is damaged or improperly formed due to genetic defects, a host of neurological symptoms may arise. A rare form of peripheral neuropathy in Tangier disease (TD) patients is associated with autosomal recessive mutations in ABCA1. Accordingly, when ABCA1 loses its function due to misexpression, the neuropathic phenotype is over-represented. Independently, studies have revealed the altered expression of ABCA1 and dysregulation of cholesterol metabolism in a host of inherited peripheral neuropathies engaging the Peripheral Myelin Protein 22 (PMP22), suggesting shared pathophysiology. While the role of ABCA1 has not been investigated broadly in peripheral nerves, the transporter molecule is a therapeutic target for human disorders, including multiple sclerosis and Alzheimer’s disease. Investigations in rodent models of type 1 Charcot–Marie–Tooth (CMT) neuropathies support the candidacy of this cholesterol transporter as a therapeutic target in efforts of peripheral myelin repair. Ongoing preclinical studies in central and peripheral nervous system disease models will provide critical information on the importance of ABCA1 as a target for disease modifying intervention. Full article

The interaction between chrono-nutrition (dinner intake), glycemic index (GI), and the C358A variant of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), along with its impact on morning fasting insulin and glycemia, has not been previously explored. This study provides new insights into chronometabolic and nutrigenetic interactions. This study aims to analyze the association between the dinner GI and the C385A variant in the FAAH gene with respect to fasting glucose, insulin levels, and HOMA-IR in adults with obesity. It was hypothesized that the dinner GI, probably influenced by the FAAH variant, could be associated with glycemic homeostasis in adults with obesity. This is a secondary analysis of a cross-sectional study focused on 189 adults with obesity (129 women; mean age, 41 ± 12 years; mean BMI, 38.0 ± 5.2 kg/m²). Dietary intake was assessed through two 24 h food records, enabling the calculation of GI and macronutrient composition at each meal, especially dinner. Fasting-parameter setting and genotyping were done during the study. The lineal regression analyses were adjusted by age, sex, BMI, energy intake and dinner protein. Participants with lower fasting glucose levels had higher total GI and dinner GI values than those with higher fasting glucose levels, whereas no differences in dinner GI were observed across groups stratified by insulin or HOMA-IR levels. In fully adjusted regression models, dinner GI values remained inversely associated with fasting glucose levels (β = −0.172, 95%CI −0.298 to −0.045; p = 0.008). The FAAH C385A variant independently predicted lower insulin (β = −2.674, 95%CI −5.185 to −0.164; p = 0.037) and lower HOMA-IR (β = −0.731, 95%CI −1.364 to −0.099; p = 0.024) levels. No statistically significant interaction between dinner GI and the FAAH genotype was detected with respect to glycemia, insulin, and HOMA-IR. Overall, these findings indicate that the dinner GI influences fasting glucose levels in adults with obesity; the FAAH variant predicted lower insulin and HOMA-IR levels, supporting a plausible chrono-nutrigenetic interaction between carbohydrate quality, mealtime intake, and FAAH variation in metabolic regulation, which must be further studied. Full article

Obesity is associated with profound metabolic, inflammatory, and neurobehavioral dysfunctions. Dietary interventions leading to weight loss are commonly employed, yet it remains unclear whether all obesity-related alterations are fully reversed upon reaching normal body weight. Poor adherence to dietary regimens often results in weight cycling, or yo-yo dieting, characterized by repeated episodes of weight gain and loss, a phenomenon linked to adverse health outcomes. Here, we investigated the consequences of weight cycling in C57BL/6J mice. The Control Group was maintained on a standard chow diet throughout the protocol, whereas the experimental group underwent two alternating cycles of high-fat diet feeding (weight gain) and standard diet reversion (weight loss), until the end of the protocol where both groups reached 80 weeks of age. Despite achieving a final body weight and glucose and lipid metabolic profile comparable to lean controls, weight-cycled mice exhibited impaired sensorimotor function, increased anxiety-like behavior (evaluated through behavioral tests), and persistent inflammation, including a peritoneal macrophage pro-inflammatory profile and adipose tissue infiltration. We define this phenomenon as “obesogenic inflammatory memory”, highlighting that obesity leaves an immunological imprint that sustains inflammation even after normalization of weight and metabolic parameters. These findings demonstrate that weight cycling is associated with chronic macrophage-mediated inflammatory states, linked to long-term behavioral and neurological manifestations, and opening new avenues for future investigation and therapeutic approaches. Full article

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by vascular remodeling and right ventricular (RV) failure. Recently, attention to lipid metabolism in PH has revealed multiple mechanisms that drive disease progression, including alterations in energy supply, oxidative stress, inflammatory signaling, and epigenetic regulation. Notably, lipid metabolism in PH exhibits marked spatiotemporal heterogeneity. This creates a therapeutic paradox in which the same metabolic intervention may exert opposing effects depending on tissue type and disease stage. Despite these challenges, targeting lipid metabolism remains an attractive therapeutic strategy. Preclinical and early clinical studies suggest that both small-molecule metabolic modulators and natural compounds hold promise for reversing pulmonary vascular remodeling and improving RV function. This review summarizes current advances in lipid metabolic reprogramming in PH and highlights the challenges of developing tissue- and time-specific interventions. Full article

Pentadecanoic acid (C15:0) is an odd-chain fatty acid (OCFA) with significant health benefits, mainly produced by microbial fermentation. To improve C15:0 production, this study compared the effects of different alcohols on C15:0 production in Yarrowia lipolytica CICC1778, identified 1-propanol as the most effective precursor, assessed its optimal concentration, and employed transcriptomic and metabolomic analyses to elucidate the regulatory mechanisms. The results showed that supplementation with 0.5% 1-propanol resulted in a total lipid production of 1.54 g/L in Y. lipolytica CICC1778, showing no differences compared with the negative control (NC) group, while C15:0 production increased to 76.68 mg/L, representing a 794.7% increase compared with the NC group. Integrated omics analysis showed that propionylcarnitine was positively correlated with ADH2, ADH1, ACADSB, ALDH6A1, and CAT2; O-methylmalonylcarnitine was positively correlated with IVD, MCCC2, ACADSB, and ALDH6A1; and (R)-leucic acid and 2-hydroxy-3-methylbutyric acid were positively correlated with IVD, BAT2, MCCC2, and ACADSB and ALDH6A1 and BAT2, respectively. All of these DEGs and DEMs were upregulated in the alcohol-treated (ALC; supplementation with 0.5% 1-propanol) group. Taken together, supplementation with 0.5% 1-propanol was an effective strategy for enhancing C15:0 production in Y. lipolytica CICC1778; 1-propanol underwent dehydrogenation-oxidation and promoted branched-chain amino acid degradation to expand the propionyl-CoA pool, thereby facilitating C15:0 synthesis. Full article

Quinone/hydroquinone couples play a crucial role in a variety of biochemical processes and chemical syntheses. Extending from our previous work, a practical dataset including the thermodynamic driving forces of 12 chemical processes for 118 quinone/hydroquinone couples accepting or releasing two hydrogen atoms in DMSO is established. The dataset serves as a foundation for assessing and discussing the thermodynamic capabilities of hydroquinones acting as two-hydrogen-atoms antioxidants or radical quenchers, quinones and semiquinone radicals acting as hydrogen atoms abstractors, and quinone/hydroquinone couples acting as dehydrogenation and hydrogenation reagents. The fundamental thermodynamic knowledge is expected to further promote the broader application of quinone/hydroquinone couples in the field of chemical antioxidation and redox reactions. Full article

Kisspeptin is a neuropeptide recognised for a pivotal role within the reproductive system, but potentially important endocrine metabolic effects are less well understood. We examined effects of twice-daily intraperitoneal administration of saline vehicle or kisspeptin-10 (25 nmol/kg), for 21 days, on glucose homeostasis, energy balance, circulating hormones as well as the morphology-function of enteroendocrine and islet cells in high-fat diet (HFD) fed female mice, with normal diet (ND) mice as an additional control group. Kisspeptin-10 decreased body weight, blood glucose and energy intake to ND levels. HFD increased circulating follicle-stimulating hormone (FSH) levels, which were further enhanced by kisspeptin-10 along with luteinising hormone (LH) concentrations. Neither HFD nor kisspeptin-10 affected progesterone or corticosterone. In the ileum, kisspeptin-10 decreased crypt depth and restored villi length to ND control levels, as well as increasing the proportion of glucose-dependent insulinotropic polypeptide (GIP) positive cells when compared to HFD mice and glucagon-like peptide-1 (GLP-1) positive cells compared to ND mice. Peptide YY (PYY) immunoreactivity was unaltered by HFD or kisspeptin-10. Plasma GIP was unchanged but circulating GLP-1 and PYY were reduced to ND levels. Within the pancreas, total islet, beta- and alpha-cell areas were similar in all mice, but kisspeptin-10 intervention restored relative insulin area to ND levels. Glucagon radius, an indicator of peripherally located alpha-cells, was reduced in HFD mice but normalised by kisspeptin-10 alongside elevated glucagon-islet area. Notably, beta-cell proliferation was increased by kisspeptin-10 with no alteration in beta-cell apoptosis. Overall, we reveal a previously uncharacterised diverse metabolic role for kisspeptin in directly modulating the gut–pancreatic axis. Full article

This study aimed to investigate whether knockout of the ApoB48 gene improves lipid metabolism disorders induced by a high-fat diet (HFD) in mice. Clustered regularly interspaced short palindromic repeats–Cas9 gene editing technology was used to knock out the ApoB48 gene in C57BL/6J mice, and genotype identification showed heterozygosity (HE, ApoB48 +/−). Subsequently, eight HE and eight wild-type (WT) mice were fed a HFD for 12 weeks. Fasting blood glucose, and insulin levels were decreased in ApoB48 +/− mice. The intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test showed mild insulin resistance. Moreover, it delayed the development of atherosclerosis and intestinal tissue damage. Differential metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate were identified using liquid chromatography–mass spectrometry, and differentially expressed proteins, including ceramide synthase 6 (CerS6), protein phosphatase 2A (PP2A), and protein kinase B (AKT), were indicated by the Kyoto Encyclopaedia of Genes and Genomes. Therefore, decreased expression of ApoB48 can ameliorate lipid metabolism disorders induced by an HFD, which may be related to the CerS6/PP2A/AKT pathway. This might represent a new approach for exploring methods to treat hyperlipidaemia. Full article

The structure and function of high-density lipoprotein (HDL), rather than its concentration, are more important factors in determining HDL activity. HDL particles (HDL-P) are heterogeneous in their composition, size, and antioxidative function. We investigated the levels of HDL subfractions and oxidized high-density lipoprotein (Ox-HDL) and validated their correlation with genetic determinants underlying peripheral artery disease (PAD). We recruited a PAD population stratified by claudication severity (group I) and critical limb ischemia (group II) according to the Rutherford classification. We found that the level of Ox-HDL was significantly increased with Rutherford classification (group II; p = 0.001). Conversely, the levels of high-density lipoprotein cholesterol (HDL-C), HDL-P, and small high-density lipoprotein particles (S-HDL-P) were significantly reduced in group II. Three single nucleotide polymorphisms (SNPs) were differentially associated with HDL particles and Ox-HDL. Briefly, rs117685211 and rs7934858 showed opposing effects, with rs117685211 and rs148877054 being associated with low levels of HDL subfractions; rs148877054 was significantly associated with M and S-HDL-P. Our study indicated the significance of HDL subfractions and Ox-HDL in the pathogenesis of PAD. Full article

Breast cancer (BC) is a primary cause of cancer-related mortality in women, making the development of novel therapeutic strategies essential. Altered lipid metabolism is a recognized hallmark of cancer, presenting a key therapeutic vulnerability. This study investigated the cytotoxic effects of the natural phenolic compound 2,3-DHBA on MCF-7 (luminal A) and MDA-MB-231 (triple-negative) human breast cancer cells and characterized the associated changes in their lipid profiles via an untargeted lipidomic approach. The in vitro cytotoxicity of 2,3-DHBA was assessed using the MTT assay at 24, 48, and 72 h against both cancer cell lines and non-cancerous L-929 fibroblasts. Following treatment with the 48-h IC₅₀ concentrations (8.61 mM for MCF-7, 5.84 mM for MDA-MB-231), total lipids were extracted and analyzed. The results showed that 2,3-DHBA exerted potent time- and dose-dependent cytotoxic effects against both BC cell lines, with significantly higher selectivity for cancer cells over healthy fibroblasts. The more aggressive MDA-MB-231 line exhibited greater sensitivity. The lipidomic analysis revealed that 2,3-DHBA induced profound cell-specific alterations across all major lipid classes, including fatty acids, glycerolipids (GLs), glycerophospholipids (GPs), and sphingolipids (SPs). These changes suggest a multi-pronged mechanism involving the disruption of membrane integrity through GP remodeling, the attenuation of survival signaling via the GL network, and a critical shift in the sphingolipid rheostat towards pro-apoptotic ceramide accumulation. This study establishes a direct link between the cytotoxic activity of 2,3-DHBA and its ability to comprehensively reprogram the cancer cell lipidome, highlighting its potential as a sophisticated metabolic modulator for breast cancer therapy. Full article

Psychotic and affective disorders, including schizophrenia (SCZ) and depression (MDD), affect millions of people globally. The overlapping symptoms of these diseases and the lack of objective diagnostic tools could lead to misdiagnosis. Recent studies suggest that the analysis of plasma lipid levels may help to develop new diagnostic tools. In this study, we investigated the plasma lipidome of psychiatric patients and healthy controls to identify disease-specific lipid species. Using untargeted mass spectrometry, we profiled blood plasma lipids from 416 patients with common psychotic and affective disorders and 272 healthy individuals from two different cohorts. We observed lipidome alterations in SCZ and MDD consistent with earlier findings. In total, 144 lipids showed significant changes, with 107 of them being concordant across both disorders, and 37 being discordant. Lipids that differentiated SCZ from MDD were mainly triacylglycerols with polyunsaturated fatty acid residues decreased in MDD. In an additional group of 111 patients with bipolar, schizotypal, and schizoaffective disorders, these lipid markers suggested a trend toward separating psychotic and affective disorders. Furthermore, a logistic regression model trained on lipid data distinguished SCZ from MDD with an ROC AUC of 0.83. Taken together, these results suggest that blood lipid profiling may aid in the objective differentiation of psychotic and affective disorders. Full article