搜索结果：Biochimica et biophysica acta. Molecular and cell biology of lipids

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract with a high impact on patients' quality of life. The endocannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA) are important modulators of inflammation. Their metabolism by cyclooxygenase (COX)-2 produces prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs) that are endogenous analogues of the arachidonic acid-derived prostaglandins. Several PG-G and PG-EA possess interesting biological properties, notably in the context of colitis as we reported for PGD2-G. However, while the properties of prostaglandins (such as PGE2) on epithelial cells in the context of colon inflammation are well described, the biological effects of PG-Gs and PG-EAs are unknown. Here we used Caco-2 spheroids and mouse colon organoids to evaluate how PG-Gs and PG-EAs modulate three epithelial hallmarks of colitis, namely the epithelial barrier integrity, the production of cytokines, and the wound healing process. Importantly, we tested the corresponding prostaglandins in parallel. When analyzing the effects of these prostanoids on the production of pro-inflammatory cytokines, we found that PGD2-G did decrease the production of TNFα and MCP-1 in activated Caco-2 spheroids. On colon organoids, PGE2-G modulated the levels of TNFα, MIP2α, and KC and improved the survival of colon organoids in a DSS-plating efficiency assay without affecting stem cell dynamics. Our results put forth differential effects for PG-Gs, PG-EAs and the corresponding prostaglandins, and suggest that PGE2-G could be an interesting lipid mediator in the context of colon epithelium inflammation.

The inherent heterogeneity of adipose-derived stem cells (ADSCs) complicates their characterization, as aggregated data obscure the nuanced states of individual cells and are skewed by dominant functional subpopulations affecting genetic and biological profiles. This heterogeneity presents a significant challenge for the effective deployment of ADSCs in clinical and research settings, highlighting the necessity for precise identification and isolation of specific subsets according to stringent criteria. Using single-cell RNA + ATAC multi-omics technology, we sequenced ADSCs derived from human adipose tissue through extraction, culture, and purification. This analysis identified three distinct subsets-proliferative, functional, and senescent-each exhibiting unique stemness properties. Notably, within the functional subset, cluster 6 emerged as a prime candidate for cellular engineering, showcasing robust stemness, high proliferative capacity, and low senescence. Our findings also reveal ADSCs' predisposition toward neuro-lineage differentiation, with their spatial distribution reflecting developmental trajectories and biological functions. In-depth analysis uncovered subset-specific genes with unique chromatin accessibility patterns, critical for targeted differentiation. Significantly, stemness markers BNC2 and HMGA2 were identified as indicators of non-senescent ADSCs. Through single-cell multi-omics sequencing, we have mapped a comprehensive cellular atlas of ADSCs, elucidating their transcriptional and chromatin profiles to unravel their complex heterogeneity. This atlas not only elucidates variations in composition, function, stemness, and developmental stages across subsets but also identifies essential biomarkers for ADSCs quality control, establishing a robust foundation for advancing ADSC-based therapeutic strategies.

Dysregulated lipid metabolism drives atherosclerosis (AS). Yacon, an Andean lipid-modulating tuber, exerts anti-AS potential, but mechanisms remain unclear. We integrated network pharmacology, machine learning, single-cell RNA sequencing (scRNA-seq), and in vivo validation to explore its anti-AS effects and targets. Active constituents and targets were curated from literature, TCMSP, and SwissTargetPrediction; lipid/AS genes from GeneCards, OMIM, and GEO were filtered via limma, WGCNA, LASSO, randomForest, and SVM-RFE. Immune infiltration and external validation confirmed hub gene relevance. scRNA-seq prioritized FABP5; docking and dynamics quantified compound-FABP5 interactions. In vivo efficacy was tested in high-fat diet (HFD)-fed ApoE-/- mice via histology (Oil Red O, H&E, and Masson) and molecular assays (RT-qPCR, Western blot, and immunofluorescence). We identified 12 constituents, 384 targets, and seven core targets (AURKA, MMP9, FABP5, etc.), with FABP5 top-ranked. Docking and dynamics identified Enhydrin as the strongest FABP5 binder. Enhydrin administration was associated with reduced hepatic lipid accumulation, decreased serum triacylglycerol (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, and increased high-density lipoprotein cholesterol (HDLC) levels. Histopathological analysis of arterial tissues revealed attenuated vascular lipid deposition and delayed atherosclerotic lesion progression. Across assays, Enhydrin downregulated FABP5, reduced abnormal fatty acid trafficking, and upregulated PPARγ and ABCA1, with markedly reduced vascular lipid deposition and improved serum lipid profiles, reflecting enhanced cholesterol efflux. Conclusion: Our integrative multi-omics analysis pinpointed FABP5 as a promising novel target for yacon-derived Enhydrin in atherosclerosis. In vivo, Enhydrin markedly downregulated FABP5 and upregulated PPARγ and ABCA1, suggesting this axis mediates its anti-atherosclerotic activity. SIGNIFICANCE STATEMENT: 1: This study identified FABP5 as a candidate target for atherosclerosis through integrative multi-omics, and its association with the anti-atherosclerotic effects of Enhydrin suggests therapeutic potential. 2: The anti-atherosclerotic effects of yacon's active components and their underlying molecular pathways were systematically screened and preliminarily characterized by integrating bioinformatic prediction with in vivo validation, laying a preliminary theoretical foundation for further pharmacological investigation and clinical translation.

The increasing global demand for aquaculture products requires sustainable fish feed strategies. This study investigated how replacing fish oil with microbial oil (MO) and canola oil (CO) combinations affects lipid metabolism and gene expression in Atlantic salmon (Salmo salar), correlating these changes with phospholipid profiles. Four isonitrogenous, isoenergetic diets were tested: 20% fish oil (FO); 10% fish oil +10% CO (FO/CO); 15% CO + 5% MO (CO/MO); and 10% CO + 10% MO (MO-10). After 16 weeks, liver and skeletal muscle tissues were sampled for lipidomics and gene expression analysis. Multivariate analysis revealed distinct dietary group separations. The CO/MO diet induced the highest hepatic expression of de novo lipogenesis gene fatty acid synthase b while suppressing fatty acid oxidation marker acyl-CoA oxidase 1, indicating lipid storage promotion. Inflammatory marker arachidonate 12-lipoxygenase was associated with groups with reduced ω3 LC-PUFA (FO/CO, CO/MO). Muscle tissue showed subtler but diet-specific gene expression patterns, with de novo lipogenesis genes (stearoyl-CoA desaturase b, ATP citrate lyase 2) associated with decreased ω3 LC-PUFA (i.e., EPA and DHA) and correlating with monounsaturated fatty acids. The MO-10 group mirrored FO-fed fish, demonstrating successful fish oil replacement at 10% inclusion. Lipidomic pathway analysis revealed diet-induced phospholipid remodelling, for example, enhanced PE-to-PC conversion in the FO/CO and CO/MO groups, suggesting membrane-fluidity and inflammatory modulation. These results demonstrate tissue-specific metabolic adaptations to alternative lipid sources, with 10% CO + 10% MO effectively substituting for fish oil while maintaining metabolic profiles in the trial timeline. The findings advance our understanding of lipid metabolism regulation in salmon and support sustainable feed development for aquaculture and enhanced nutritional quality of aquaculture products.

The lipid abnormalities are observed in pregnant women with normal glucose tolerance (NGT) and those diagnosed with gestational diabetes mellitus (GDM), but in the latter, they are intensified and may indicate underlying metabolic dysfunction that transiently manifests during pregnancy. Due to the complex relationship between lipid metabolism and glucose regulation, alterations in lipoproteins may act as preliminary biomarkers for the early detection and monitoring of GDM and postpartum changes. In the current study, we performed a 1H NMR analysis of plasma lipoproteins in the cohort comprising pregnant NGT women and those diagnosed with GDM at three critical time points: 24-28 gestation week and 3 and 12 months postpartum. After assignment of lipoprotein-associated signals in NMR spectra, Partial Least Squares Discriminant Analysis (PLS-DA) revealed clear distinctions between NGT and GDM groups. Correlation analysis revealed a moderate negative correlation of CH3VLDL, a moderate positive correlations of CH2CH2C=C with 2 h-OGTT and 1 h-OGTT, and a significant negative correlation of CH3VLDL, and a positive correlation of CH2CH2C=C were noted for HOMA IR. At the 3-months mark, the concentrations of (CH2)n LDL, CH2CH2CH2CO VLDL, all unsaturated lipids, and (CH=CH) LDL + VLDL, CH2/CH3 LDL + VLDL, and CH=CH/CH3 LDL + VLDL were decreased, while the concentrations of (C18 VLDL, CH3 LDL, CH2CH2C=C, CH2C=C, CH2CO, C=CCH2C=C, choline N(CH3)3, glyceryl CH2OCOR) were increased. The concentrations of selected fractions at the 1-year postpartum time point remained unchanged. Our findings provide essential insights into lipoprotein dysregulation in GDM and underscore possible implications for early intervention and long-term metabolic risk reduction for maternal health.

Fibroblast growth factor 19 (FGF19) is a key intestinally secreted factor in mammals, its physiological role in teleost remains largely unclear. This study aimed to investigate the function and underlying mechanisms of FGF19 in the regulation of lipid metabolism in large yellow croaker. Results revealed that FGF19 was predominantly expressed in the liver. Treatment with recombinant FGF19 protein significantly reduced triglyceride (TG) levels in hepatocytes in a dose-dependent manner. Both in vitro treatment and in vivo injection of FGF19 significantly downregulated lipogenic genes and upregulated lipolytic genes expression in hepatocytes and liver tissue. Further investigation demonstrated that FGFR1 inhibition attenuated the TG-lowering effects of FGF19 and reversed the suppression of lipogenic gene expression. Additionally, FGF19 treatment enhanced the phosphorylation of ERK, P38, AMPK, and AKT. Inhibition of P38, AMPK, or AKT significantly increased triglyceride levels which were reduced by FGF19. Inhibition of ERK, P38, and AKT impaired the FGF19-mediated regulation of lipolysis-related genes, whereas AMPK inhibition predominantly affected the regulation of lipogenic genes. Moreover, results showed that high linoleic acid (LA) intake induced endoplasmic reticulum stress and elevated expression of FGF19. The expression of XBP1s protein was significantly increased by LA treatment, while co-expression of XBP1s significantly induced the promoter activity of FGF19. In summary, these results suggest that FGF19 is primarily expressed in the liver and plays a crucial role in regulating lipid metabolism to prevent excessive lipid accumulation in large yellow croaker, while high LA intake can increase FGF19 expression through ER stress-induced XBP1s. This study will enhance the understanding of FGF19 in lipid metabolism, offering insights into the evolution of these processes in vertebrates.

In recent years, the immunomodulatory role of adipose tissue (AT) has gained attention, yet the metabolic basis for immune homeostasis in AT remains unclear. Catecholamines (CAs) activate adipocyte β3-adrenergic receptors (β3-AR) to promote lipid metabolism, while cholesterol metabolism has bidirectional immunoregulatory properties. Whether the interaction between CAs and cholesterol regulates immune function in AT is unknown. Using chickens as models, we induced distinct immune states via dexamethasone (Dex) treatment and Newcastle disease virus (NDV) vaccination. Through qRT-PCR and metabolomics, we analyzed dynamic changes in lymphocytes, CAs, and cholesterol metabolism in AT. The results indicated that B cells were present in chicken AT and positively responded to different immune states through up-regulation. AT positively responded to Dex-induced immunosuppression (DIIS) and NDV-induced immune responses by altering cholesterol and CAs metabolisms. Moreover, the differences in cholesterol and CAs metabolisms were the key ways by which Dex affected immune response in AT. AT could synthesize bile acids and steroid derivatives, and secondary immunization possible was the key stage with active changes in cholesterol derivatives in AT. We identified a circuit pathway: "lymphocyte-catecholamine-adipocyte-cholesterol-cholesterol derivatives-lymphocyte," which may underpin immune microenvironment homeostasis in AT. Additionally, miR-206 was actively involved in the processes of DIIS, and the miR-206/MSMO1 pathway potentially regulated cholesterol metabolism in AT. This study provides a perspective for in-depth understanding of the immune regulation mechanism of AT and offer a direction for developing cholesterol derivatives for immune regulation.

Polymethylene-interrupted fatty acids (PMI-FA) represent a structurally unusual class of polyunsaturated fatty acids characterised by double bonds separated by two or more methylene groups. Among them, Δ7-desaturated C22 PMI-FA are widely detected in marine invertebrates. Previous metabolic studies and fatty acid compositional data suggest that these compounds are produced via elongation of Δ5-desaturated C20 PMI-FA, but the specific enzymes and molecular mechanisms responsible for this pathway remain unclear. In this study, we investigated the enzymatic basis underlying the biosynthesis of Δ7-desaturated C22 PMI-FA across marine invertebrates. Candidate Δ5 desaturases (FadsA) and fatty acid elongases (Elovl) were identified from representative species of echinoderms, molluscs and annelids, and their activities were functionally characterised using a heterologous yeast expression system. By reconstituting the sequential Δ5 desaturation-elongation steps through co-expression of FadsA and Elovl enzymes, we demonstrate that invertebrate enzymes possess the capability to convert common C20 fatty acid precursors (20:1n-7, 20:1n-9, 20:2n-6, and 20:3n-3) into C22 PMI-FA. Our results provide direct functional support for proposed biosynthetic pathways of Δ7-desaturated C22 PMI-FA and reveal substantial interspecific variation in biosynthetic capacity among marine invertebrate lineages. These findings establish a molecular framework for understanding the widespread occurrence of PMI-FA in marine invertebrates and highlight the evolutionary flexibility and pleiotropy of fatty acid biosynthetic enzymes. Collectively, this study advances current knowledge of fatty acid biosynthesis beyond canonical ω3 and ω6 pathways and expands our understanding of fatty acid biosynthetic diversity in marine invertebrates.

Dyslipidemia is a major risk factor for the development of atherosclerosis, cardiovascular diseases, and brain injury. Berberine (BER), a type of isoquinoline alkaloid, has the potential to enhance mitochondrial performance owing to its remarkable antioxidant properties. This study aimed to explore how berberine-loaded niosomes (BER-NIO) would alleviate the adverse effects of brain injury in dyslipidemic rats. Hence, for this purpose, the genes of electron transport chain, mitochondrial dynamics, mitophagy, and apoptosis were assessed in brain tissue. Moreover, molecular docking analysis was done to predict this target pathway. Thirty-five male Sprague Dawley rats were separated into five groups: (I) Control (Ctl), (II) Poloxamer 407 (Plx), (III) Plx + BER-NIO, (IV) Plx + NC, and (V) Plx + BER-NIO + NC. BER-NIO improved lipid profile, brain MDA, and brain total antioxidant capacity (TAC) compared to Plx group. Moreover, BER-NIO was able to notably restore the activity of mitochondrial respiratory chain complexes through upregulation of the mRNA expression levels of Ndufs1, Sdhc, Coq8a, Cox6a2 and Atp5f1a. It also enhanced the mitochondrial dynamics via modulation of the transcriptional level of DRP-1, MFN-1, and MFN-2. In addition, administration of BER-NIO to dyslipidemic rats regulated the mitophagy pathway through alteration of PINK-1/Prkn pathway within brain tissue. Furthermore, BER-NIO notably enhanced neurological function through reduction of brain pathological alterations, suppression of apoptosis and decrease of the biomarker for brain injury (GFAP). Interestingly, molecular docking analysis revealed a strong binding affinity between BER and MFN-2, PINK-1 and caspase-3. The findings suggested that the BER-NIO is effective in the reduction of brain injury in dyslipidemic rats via modulation of brain oxidant/antioxidant status and mitochondrial functions.

Caveolin-2 (CAV2) is a lipid droplet (LD)-associated protein. Its role in oral leukoplakia (OLK), an oral potentially malignant disorder, and the underlying lipid metabolism mechanisms remain unclear. CAV2 conditional knockout (cKO; CAV2flox/flox; K14-Cre) and control (Flox) C57BL/6 mice were used to establish OLK models via 4-nitroquinoline-N-oxide (4NQO). A subset received a high-fat diet (HFD). Oil red O staining, RNA sequencing, multiplex immunofluorescence (Ki-67, E-cadherin, Perilipin-1, FABP5), ELISA (acetyl-CoA), serum biochemistry (ALT, TG), and targeted GC-MS/MS fatty acid profiling were performed. CAV2 knockout significantly suppressed OLK progression, evidenced by reduced lesion diameter/number and attenuated pathological severity. HFD failed to rescue OLK progression. RNA-seq confirmed dysregulation of lipid transport, lipolysis, and fatty acid metabolism/biosynthesis. Targeted metabolomics revealed markedly attenuated carcinogen-induced fatty acid accumulation in cKO mice, with C18:2n6c (linoleic acid, LA) identified as the sole metabolite showing significant genotype-dependent reduction under 4NQO challenge. cKO mice exhibited downregulated Perilipin-1 and Ki-67, and upregulated FABP5 and E-cadherin. CAV2 knockout also induced lesion acetyl-CoA accumulation and systemic lipid metabolism abnormalities. CAV2 knockout inhibits OLK formation and progression by disrupting lipid metabolism homeostasis, including restriction of LA bioavailability. Exogenous fatty acid supplementation failed to rescue OLK progression or restore metabolic homeostasis, highlighting CAV2 as a potential therapeutic target.

Punicalagin (PUN), the main bioactive in pomegranate peel polyphenols, plays a key therapeutic effect against diverse ailments, especially inflammatory diseases. Advanced Glycation End Products (AGEs) can disrupt lipid metabolism, trigger inflammation, and are closely linked to metabolic inflammatory diseases. Based on PUN's known protective effects, this study uses lipidomic analysis to examine its influence on AGEs-induced metabolic inflammation, providing a basis for anti-inflammatory drug research. To develop the medicinal value of PUN by studying its effects on AGEs-induced inflammation and lipid metabolism disorders. RAW264.7 macrophages were first stimulated with AGEs (200 μg/mL), followed by treatment with PUN (25-100 μg/mL). Next, TNF-α and IL-1β levels were measured by ELISA. Western blotting was then performed to assess the expression of PPARγ and key proteins in the NF-κB and JNK signaling pathways, nuclear translocation of NF-κB p65 was visualized via immunofluorescence. By using the antagonist GW9662, the upstream and downstream relationship between PPARγ and NF-κB, as well as JNK, was demonstrated. Finally, non-targeted lipidomics using UPLC-Q/TOF-MS, combined with PCA and OPLS-DA multivariate analysis, identified differential lipid metabolites. PUN significantly suppressed AGEs-induced secretion of TNF-α and IL-1β in a concentration-dependent manner. Mechanistically, PUN upregulated PPARγ expression, inhibited the phosphorylation of IKKα/β, IκB-α, and NF-κB, reduced p-JNK, c-Jun, and c-Fos levels, and blocked nuclear translocation of p65. The use of the PPARγ antagonist GW9662 led to a re-upregulation of the phosphorylation levels of the NF-κB and JNK pathways downstream of PPARγ. The original inhibitory effect of PUN was blocked. This confirmed that the anti-inflammatory mechanism of PUN depends on the activation of PPARγ. Lipidomics analysis revealed that PUN reversed 31 dysregulated lipid metabolites induced by AGEs, with glycerophospholipid metabolism identified as the most significantly enriched pathway. This study demonstrates that PUN alleviates AGEs-induced inflammation by restoring glycerophospholipid metabolism homeostasis, upregulating PPARγ expression, and subsequently suppressing NF-κB and JNK signaling pathways.

Despite advances in understanding metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, effective therapeutic targets remain limited. This study aimed to identify novel regulatory mechanisms by investigating the role of the RNA demethylase FTO in hepatic lipid metabolism. MASLD models were established using high-fat diet-fed mice. The expression of m6A modifying enzymes in liver tissue and the overall m6A levels were measured. Lipid deposition was assessed by Oil Red O staining in free fatty acid (FFA)-treated human hepatocytes. The interaction between FTO and HNF1A was explored by co-immunoprecipitation and luciferase reporter assays. Time course experiments evaluated the dynamic changes of m6A and oxidative stress responses. Rescue experiments were performed to verify the functional relationship between FTO and HNF1A. FTO expression was significantly upregulated in the MASLD mouse model, and FTO deficiency significantly increased liver m6A levels. Knockdown of FTO in hepatocytes reduced lipid accumulation and apoptosis. FTO regulates the expression of downstream lipogenic genes via HNF1A, without altering their m6A modification levels. Clinical samples confirmed that FTO was negatively correlated with HNF1A expression. The effects of FTO were significantly reversed by HNF1A knockdown, including lipid droplet generation, cell survival, liver steatosis, and blood metabolic indicators in mice. Our findings identify FTO as a key driver of MASLD progression via m6A-dependent regulation of HNF1A, highlighting the FTO-HNF1A axis as a potential therapeutic target.

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are central downstream effectors of the Hippo pathway and play key roles in hepatic metabolic regulation. However, the molecular mechanisms by which YAP/TAZ modulate lipid processing in hepatocytes remain incompletely understood. In this study, we investigated a YAP/TAZ-dependent non-coding RNA regulatory network controlling low-density lipoprotein receptor (LDLR) expression and lipid droplet accumulation in human hepatic cells. Using transcriptomic profiling combined with functional validation in human hepatocellular carcinoma cells, we identified the long non-coding RNA Shwachman-Bodian-Diamond Syndrome Pseudogene 1 (SBDSP1) as a YAP/TAZ-downstream transcript that positively regulates LDLR expression. Silencing of YAP/TAZ significantly reduced SBDSP1 levels, accompanied by downregulation of LDLR mRNA and protein, impaired LDL uptake, and reduced intracellular lipid droplet accumulation. Mechanistically, SBDSP1 was predicted to interact with miR-29a-5p, a microRNA putatively targeting the 3' untranslated region of LDLR. Knockdown of SBDSP1 or mimicking of miR-29a-5p decreased LDLR expression and reduced lipid accumulation, while luciferase reporter assays confirmed direct interactions between miR-29a-5p and both SBDSP1 and LDLR. Collectively, these findings describe a potential YAP/TAZ-SBDSP1-miR-29a-5p-LDLR regulatory axis that controls hepatic lipid uptake and accumulation. This study provides molecular insights into the interplay between Hippo pathway signaling and non-coding RNA networks to regulate lipid metabolism, highlighting a potential regulatory mechanism that may be relevant to hepatic lipid accumulation in metabolic dysfunction-associated steatotic liver disease.

Hypertension is a major contributor to cardiovascular diseases and all-cause mortality worldwide. It can cause damage to multiple target organs, with the kidneys being particularly susceptible. Conditional knockdown of methyltransferase-like 3 (METTL3), an enzyme that mediates N6-methyladenosine modification, has been shown to improve cardiovascular remodeling and reduce blood pressure; however, the underlying mechanisms remain unclear. In this study, we investigated how METTL3 influences hypertension using integrated proteomic and metabolomic analyses. METTL3-knockdown mice were treated with angiotensin II to induce hypertension, followed by proteomic and metabolomic profiling of kidney tissue to identify METTL3-related target proteins and pathways. Hypertension was found to upregulate METTL3 in the kidneys, disrupt fatty acid metabolism, and downregulate proteins involved in mitochondrial energy metabolism. Moreover, conditional knockdown of METTL3 in endothelial cells led to decreased blood pressure in hypertensive mice and a gradual normalization of both fatty acid and energy metabolism. Collectively, these findings suggest that hypertension-induced upregulation of METTL3 contributes to mitochondrial damage and fatty acid metabolism dysregulation. Conditional knockdown of METTL3, in contrast, mitigates mitochondrial injury, restores fatty acid metabolism, and promotes recovery from hypertensive kidney damage, highlighting METTL3 as a potential therapeutic target for hypertension.

Consumption of a high-fat diet (HFD) diet is a factor associated with several diseases including obesity and its associated complications, especially liver and kidney dysfunction via promoting derangement of lipid metabolism. It has been reported that fructooligosaccharides (FOS) improve insulin sensitivity and ectopic lipid accumulation. The aim of this study was to investigate the effects of FOS on insulin resistance, liver and renal lipid accumulation, inflammasome formation, oxidative stress and intestinal barrier integrity in an obese rat model. Male Wistar rats were fed a normal (ND) or HFD for 16 weeks. The rats given a HFD were then given FOS at 1 or 2 g/day and metformin at 30 mg/kg/day daily for 8 weeks by oral gavage. The results demonstrated that FOS and metformin improved insulin resistance. FOS showed greater efficacy than metformin in attenuating intestinal barrier leakage. FOS and metformin decreased liver lipid synthesis as evidenced by the downregulation of SREBP1c, FAS and perilipin2. Renal lipid accumulation was restored concomitant with the reduction in renal lipid content and lipotoxicity. Liver and renal inflammation and organ injury were restored to within normal limits. However, FOS had no effect on the antioxidant enzymes via KEAP1/NRF2. Metformin attenuated renal oxidative stress via the suppression of PKCα and the FOXO1 signaling pathway. These suggest that FOS and metformin have the potential to improve gut health and prevent liver and renal complications and could be used as a useful supplement in the obese condition.

Early zebrafish embryos rely on maternally supplied yolk lipids to fuel growth before the onset of feeding; yet, how these lipids are mobilized and redistributed remains poorly understood. Here, we combine live imaging with the solvatochromic dye Nile Red to map lipid composition in space and time through changes in the emission peak, a readout of local polarity. We show that lipid droplets (LDs) in the blastodisc are highly heterogeneous in size and polarity at the "one-cell stage" but progressively homogenize as development proceeds. LDs originate at the yolk-blastodisc interface, where localized lipase activity drives their biogenesis and initial composition. As LDs migrate toward the animal pole, their polarity increases, reflecting continuous lipolysis within a spatially confined metabolic zone. Smaller LDs display greater lipolytic efficiency than larger ones, linking droplet geometry to metabolic turnover. Inhibition of lipase activity disrupts both LD formation and lipid cycling, demonstrating that shared enzymatic machinery underlies droplet synthesis and degradation. Together, our findings reveal a spatially organized and developmentally regulated lipid metabolism in the zebrafish blastodisc, where local enzyme activity, droplet mechanics, and lipid composition are dynamically coupled. This live-imaging approach establishes a framework for studying lipid regulation in vertebrate development and disease. DIGEST SUMMARY: By visualizing lipids in living zebrafish embryos, this study reveals that lipid droplets are not passive fat stores but dynamic organelles whose size, composition, and behavior are shaped by local enzyme activity at the yolk-blastodisc interface, offering new insight into how developing cells control their energy reserves.

Curcumol, a bioactive constituent derived from Rhizoma Curcumae roots, possesses anti-inflammatory and anti-viral properties. This study investigated its therapeutic effects on lipophagy in hepatic stellate cells (HSCs) and lipid accumulation in hepatocytes within a model of high-fat diet-induced hepatic fibrosis, along with the underlying molecular mechanisms. Initially, curcumol treatment significantly attenuated lipid droplets (LDs) degradation and suppressed HSC activation, effects potentially associated with the inhibition of lipophagy. These outcomes were partially reversed by Rab18 overexpression, which modulates the autophagy-lysosomal pathway. Moreover, the ameliorative effect of curcumol on choline-deficient, L-amino acid-defined, 45 % high-fat diet (CDAHFD)-induced hepatic pathology was partially abolished upon Rab18 overexpression in mice. Importantly, curcumol promoted Farnesoid X receptor (FXR) expression, which inhibited the CREB/TORC2 interaction, thereby further suppressing LC3B expression and activation in LX2 cells. Additionally, curcumol impeded LD expansion and reduced lipid accumulation in palmitic acid (PA)-treated BNL-CL.2 cells and hepatocytes from CDAHFD-fed mice by inhibiting LD-endoplasmic reticulum (ER) contact formation, which could be reversed by Rab18 overexpression. In conclusion, curcumol inhibits HSC lipophagy by downregulating Rab18-mediated LD-autophagosome formation and enhancing the FXR-CREB interaction. Furthermore, it ameliorates hepatocyte lipid accumulation in fibrotic livers by disrupting Rab18-dependent LD-ER contacts. These findings underscore the therapeutic potential of curcumol in the treatment of HFD-induced hepatic fibrosis.

Myogenic differentiation plays a vital role in embryonic muscle formation, postnatal muscle regeneration and repair processes. Exogenous fatty acids (FAs) influence physiological functions of skeletal muscle. Nevertheless, our grasp of how various types of FAs influence skeletal muscle differentiation remains limited and inconsistent. In this study, we comprehensively evaluated the effects of the six prevalent FAs on metabolism, proliferation, and differentiation of skeletal muscle precursor cells. We employed C2C12 myoblasts and treated them with three saturated FAs: palmitic acid (PA), stearic acid (SA), myristic acid (MA), as well as three unsaturated FAs: docosahexaenoic acid (DHA), oleic acid (OA), linoleic acid (LA). We found OA and LA facilitated proliferation of C2C12 cells through MAPK-ERK1/2 pathway, whereas DHA and MA had a mild inhibitory effect on this process. No significant effect on cell proliferation was noted with PA or SA treatment. Interestingly, both PA and MA unexpectedly enhanced myogenic differentiation, evidenced by promoting cell cycle exit through increased p21 levels, alongside myotube formation via upregulation of myogenin and MyHC by PI3K/Akt signaling pathway. In contrast, SA and all three unsaturated FAs considerably hindered myogenic differentiation. Collectively, these findings suggest PA and MA might serve as beneficial FAs to support skeletal muscle differentiation. Furthermore, even within the same categories of FAs, such as saturated and unsaturated, their effects on myogenesis differ and may even be contradictory. This observation challenges the traditional perceptions regarding FAs and provides a novel perspective for understanding the impact of different FAs on myogenesis.

Lipid droplets (LDs) are dynamic organelles that coordinate lipid storage, trafficking, and metabolic adaptation under physiological and stress conditions. Despite their emerging role in cellular homeostasis, the molecular basis of treatment-induced lipid droplet remodeling remains insufficiently defined. Here, we combine lipid droplet isolation with label-free Raman spectroscopy to characterize biochemical and spectroscopic signatures associated with structural remodeling of isolated lipid droplets (iLDs) derived from normal Schwann cells and malignant peripheral nerve sheath tumor (MPNST) cells exposed to cannabidiol (CBD), ionizing radiation, and their combination. Our analysis reveals pronounced intrinsic spectral heterogeneity within iLD fractions and identifies treatment- and cell type-specific alterations in lipid composition, Raman spectral markers associated with acyl chain packing, and conformational order. Notably, stress-induced remodeling involves coordinated changes in lipid chain organization, highlighting lipid droplets as dynamic regulators of cellular metabolic adaptation. These findings provide molecular insight into lipid droplet-mediated stress responses and establish Raman-based profiling of isolated LDs as a powerful approach for investigating lipid remodeling mechanisms within isolated lipid droplet-enriched fractions. We further propose the Raman intensity ratio I₁₁₆₇/I₁₂₉₂ as a semiquantitative Raman-derived spectral index associated with stress-induced lipid remodeling and CBD-mediated radiosensitization.