Search Results (240)

Long non-coding RNAs (lncRNAs) interact with a variety of biomolecules, including DNA, mRNAs, microRNA, and proteins, to regulate various cellular processes. Recently, their interactions with lipids have gained increasing attention as an emerging research area. Both lipids and lncRNAs play central roles in cellular regulation, and growing evidence reveals a complex interplay between these molecules. These interactions contribute to key biological functions, such as cancer progression, lipid droplet transport, autophagy, liquid−liquid phase separation, and the formation of organelles without membranes. Understanding the lipid−lncRNA interface opens new avenues for unraveling cellular regulation and disease mechanisms, holding great potential not only for elucidating the fundamental aspects of cellular biology but also for identifying innovative therapeutic targets for metabolic disorders and cancer. This review highlights the biological relevance of lipid–lncRNA interactions by exploring their roles in cellular organization, regulation, and diseases, including metabolic and cancer-related disorders. Full article

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of liver conditions, from simple hepatic steatosis to its more severe inflammatory form known as metabolic dysfunction-associated steatohepatitis (MASH). Despite its growing clinical significance and association with cirrhosis and cancer, there are currently few pharmacological treatments available for MASLD, highlighting the urgent need for new therapeutic strategies. This narrative review aims to elucidate the molecular mechanisms of lipophagy in MASLD progression, emphasizing how its dysfunction contributes to hepatic steatosis and lipotoxicity. We also explore the intersection of lipophagy failure with oxidative stress and inflammation in the liver, focusing on key signaling pathways, such as mTORC1 and AMPK, and discuss the therapeutic potential of targeting these pathways by systematically reviewing the literature from PubMed, Scopus, and Google Scholar databases. Recent studies suggest that lipophagy, the selective autophagic degradation of lipid droplets, is crucial for maintaining hepatic lipid homeostasis. Indeed, some vital components of the lipophagy machinery seem to be functionally inhibited in MASLD, resulting in the accumulation of intracellular triacylglycerol (TAG), lipotoxicity, and subsequent oxidative stress, all of which contribute to disease progression. In summary, impaired lipophagy is a central pathological mechanism in MASLD, making it an important therapeutic target. A deeper understanding of these mechanisms may offer new strategic insights for combating the progression of MASLD/MASH. Full article

The aim of this study is to investigate the physiological characteristics and regulatory mechanisms of porcine intramuscular fat (IMF), subcutaneous fat (take back fat (BF), for example), and visceral fat (take perienteric fat (PF), for example) to address the challenge of optimizing meat quality without excessive fat deposition. Many improved breed pigs have fast growth rates, high lean meat rates, and low subcutaneous fat deposits, but they also have low IMF content, resulting in poor meat quality. There is usually a positive correlation between intramuscular fat and subcutaneous fat deposits. This study selected eight-month-old female Tibetan pigs as experimental subjects. After slaughter, fat samples were collected. Histological differences in adipocyte morphology were observed via hematoxylin–eosin (HE) staining of tissue sections, and phenotypic characteristics of different adipose tissues were analyzed through fatty acid composition determination. Transcriptome sequencing and untargeted metabolomics were employed to perform pairwise comparisons between different fatty tissues to identify differentially expressed genes and metabolites. A siRNA interference model was constructed and combined with Oil Red O staining and lipid droplet optical density measurement to investigate the regulatory role of WNT16 in adipocyte differentiation. Comparative analysis of phenotypic and fatty acid composition differences in adipocytes from different locations revealed that IMF adipocytes have significantly smaller areas and diameters compared to other fat depots and contain higher levels of monounsaturated fatty acids. Integrated transcriptomic and metabolomic analyses identified differential expression of WNT16 and L-tyrosine, both of which are involved in the melanogenesis pathway. Functional validation showed that inhibiting WNT16 in porcine preadipocytes downregulated adipogenic regulators and reduced lipid droplet accumulation. This cross-level regulatory mechanism of “phenotype detection–multi-omics analysis–gene function research” highlighted WNT16 as a potential key regulator of site-specific fat deposition, providing new molecular targets for optimizing meat quality through nutritional regulation and genetic modification. Full article

Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a lack of approved pharmacological therapies. Our previous study showed that the daily consumption of Navelina oranges significantly reduced hepatic steatosis in patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Starting with our previous study, here, we have investigated the molecular targets through which Hesperidin (HE), a citrus flavanone, is able to prevent the progression of NAFLD to NASH using an in vitro model. In Hepa-RG cells exposed to NAFLD Promoting Agents, HE reduced lipid droplet accumulation (~35%) and suppressed de novo lipogenesis, with decreased expression of FASN (0.62 ± 0.06 vs. 0.39 ± 0.03 at 100 µg/mL) and SCD1 (0.05 ± 0.001 vs. 0.03 ± 0.004 at 50 µg/mL). HE also enhanced fatty acid oxidation by increasing SIRT1 (0.73 ± 0.16 vs. 2.36 ± 0.10 at 50 µg/mL) and PGC1α (0.71 ± 0.03 vs. 0.89 ± 0.003 at 50 µg/mL). In LX-2 cells, HE downregulated COL1A1 (1.48 ± 0.10 vs. 0.90 ± 0.11 at 100 µg/mL) and α-SMA (1.21 ± 0.16 vs. 0.76 ± 0.07 at 75 µg/mL) and upregulated MMP3 (0.64 ± 0.05 vs. 0.98 ± 0.07) and MMP9 (0.99 ± 0.005 vs. 2.61 ± 0.16 at 100 µg/mL). In conclusion, HE may offer a promising approach for NAFLD/NASH prevention and treatment, demonstrating in vitro its potential to reduce hepatic steatosis and fibrosis. Full article

Sarcopenic obesity (SO) is a metabolic disorder for which no effective pharmacological treatments are currently available. Cistanoside F (Cis), a phenoxyethanol-derived compound, remains relatively unexplored in the context of lipid metabolism regulation, as well as its potential mechanisms and therapeutic applications in metabolic disorders. Consequently, this study aimed to evaluate the potential of Cis in ameliorating the pathological manifestations of SO in C2C12 cells. Two classical adipogenic differentiation models using C2C12 cells were employed to quantitatively assess the ability of Cis to inhibit lipid droplet formation, utilizing Oil Red O staining coupled with high-content imaging analysis. Markers associated with adipogenic and myogenic differentiation were examined using quantitative real-time PCR and Western blotting. Our experimental findings demonstrated that Cis significantly attenuated lipid droplet accumulation and promoted muscle protein synthesis via the modulation of PPARγ, ATGL, CPT1b, and UCP1 expression during lipogenic differentiation of C2C12 cells. Cis significantly upregulated the phosphorylation and expression levels of key metabolic regulators, including p-AMPK/AMPK, p-ACC1/ACC1, and MHC. We identified a positive regulatory feedback mechanism between AMPK signaling and MHC expression in the adipogenic differentiation model, suggesting that Cis exerts its therapeutic effects through AMPK-dependent pathways. This is the first study to provide the first experimental evidence supporting the therapeutic potential of Cis for metabolic regulation, targeting adiposity reduction and muscle mass enhancement. Furthermore, Cis exhibited potent anti-inflammatory properties, as demonstrated by its ability to significantly downregulate proinflammatory mediators, including IL-6 and p-NF-κB/NF-κB, during adipogenic differentiation. These novel findings regarding the anti-inflammatory mechanisms of Cis will form the basis for our subsequent in-depth mechanistic investigations. Full article

The protozoan parasite Toxoplasma gondii transitions between acute (tachyzoite) and chronic (bradyzoite) stages, enabling lifelong persistence in hosts. Iron depletion triggers bradyzoite differentiation, with the phosphotyrosyl phosphatase activator (PTPA) identified as a key regulator. Here, we define PTPA’s role in T. gondii pathogenesis. PTPA forms a ternary complex with PP2A A/C subunits, validated by reciprocal pull-down assays. Depleting PTPA impaired tachyzoite proliferation, invasion, and gliding motility, while stress-induced bradyzoites exhibited defective cyst formation and vacuolar swelling. Metabolic dysregulation included amylopectin accumulation and lipid droplet proliferation. The PP2A inhibitor LB-100 phenocopied PTPA depletion, suppressing tachyzoite growth and bradyzoite differentiation. TgPTPA emerges as a linchpin coordinating PP2A activity, metabolic flux, and lifecycle transitions. Its dual roles in acute virulence and chronic persistence, combined with LB-100’s efficacy, position the PTPA–PP2A axis as a promising target for antitoxoplasmosis strategies. Full article

Background/Objectives: Disruptions in adipose tissue dynamics contribute to obesity-related metabolic disorders, emphasizing the need for targeted therapies focusing on adipose tissue cells, including progenitor cells and adipocytes. Peroxisome proliferator-activated receptor gamma (PPARG) ligands are potent insulin sensitizers used in type 2 diabetes treatment. This study investigated the effects of rosiglitazone, a PPARG agonist, and betulinic acid, a PPARG antagonist, on adipogenesis and apoptosis in 3T3-L1 pre-adipocytes. Method: 3T3-L1 pre-adipocytes were treated with rosiglitazone or betulinic acid during adipogenic differentiation. Lipid droplet formation was used to evaluate adipogenesis. Cell growth and cell death were assessed using the resazurin-based cell viability assay, trypan blue exclusion assay, LDH assay, and Annexin V/PI staining. Quantitative PCR was conducted to examine the expression of genes associated with adipogenesis and apoptosis. Results: Betulinic acid reduced adipogenesis only when administered daily for eight days. Rosiglitazone did not alter the overall lipid quantity; however, it promoted a shift toward fewer but larger lipid droplets. Both compounds increased Adipoq and Cfd expression, and betulinic acid also elevated Fabp4. Rosiglitazone induced stronger cell aggregation. Despite increased cell death, overall viability was maintained. Apoptotic cell death was enhanced by both compounds and confirmed via Annexin V/PI staining and flow cytometry, accompanied by downregulation of Ccnd1 and Bcl2. Additionally, rosiglitazone markedly increased the expression of Cebpa, a key regulator that can modulate lipid droplet formation and the balance between cell growth and death. Conclusions: Rosiglitazone and betulinic acid differentially modulate adipogenesis and apoptosis in 3T3-L1 cells, revealing a complex interplay between lipid accumulation and programmed cell death. Together, the findings underscore the potential of dual PPARG-targeting approaches for metabolic disease interventions. Full article

Recent studies have demonstrated that dietary plant extracts can inhibit the development of lipid droplets (LDs) and oxidized LDs (oxLDs) in hepatic cells. These findings suggest that such extracts may be beneficial in combating metabolic dysfunction-associated fatty liver disease (MAFLD) and its more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH). We examined nine Allium extracts (ALs: AL1–9) to assess their capacity to decrease lipid droplet accumulation (LDA) and oxidative stress by suppressing lipid formation and oxidation in liver cells. Among the Allium extracts tested, AL6 exhibited significant inhibitory effects against LDA. Furthermore, we employed our lipidomic method to assess the accumulation and suppression of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] by AL6 in liver cells under oleic acid (OA) and linoleic acid (LA) loading conditions. These findings indicate that foods derived from Allium species prevent the formation of lipid droplets by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. Analysis of the metabolome of bioactive lipid droplet accumulation inhibition (LDAI) AL6 using LC-MS/MS and 1D-NMR [¹H, ¹³C, DEPT 90, and 135] techniques revealed that AL6 is primarily composed of carbohydrates, glucosidic metabolites, and organosulfur compounds, with small amounts of polyols, fatty acyls, small peptides, and amino acids. This implies that AL6 could be a valuable resource for developing functional foods and drug discovery targeting metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH) and related disorders. Full article

Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal–lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development. Full article

Objectives: HSD17B13 (17β-hydroxysteroid dehydrogenase 13), a lipid droplet-associated enzyme, has emerged as a key regulator of hepatic lipid metabolism and a potential therapeutic target for metabolic-associated fatty liver disease (MAFLD). While its role in lipid homeostasis and liver inflammation has been partially revealed, the impact of HSD17B13 deficiency on lipid metabolism in aged mice remains poorly understood. In this study, we performed comprehensive lipidomic profiling of liver tissues from aged Hsd17b13 gene knockout (Hsd17b13 KO) mice to investigate the effects of Hsd17b13 deletion on hepatic lipid composition and metabolic pathways. Methods: Changes in hepatic lipid profiles were assessed through a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomic analysis. Results: The lipid profiles, including triglycerides (TGs), diglycerides (DGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidylglycerols (PGs), and ceramides (Cers), exhibited notable alterations in the Hsd17b13 KO mice. Conclusions: HSD17B13 plays a pivotal role in liver lipid metabolism during aging, and it is involved in the regulation of hepatic phospholipid metabolism. Our study highlights the importance of HSD17B13 in maintaining liver lipid homeostasis and its potential as a therapeutic target for age-related liver diseases. Full article

Tail adipose deposition in sheep is an economically significant trait that has an impact on meat quality and reproductive performance. This study elucidates the regulatory mechanism of FGFBP1 in the proliferation and differentiation of ovine tail-derived preadipocytes. Overexpression and knockdown methods were used to establish gain- and loss-of-function models, and the biological effects of FGFBP1 on adipocyte dynamics were systematically assessed. FGFBP1 overexpression significantly inhibited cellular proliferation by cell cycle arrest in the G2/M phase, and, at the same time, promoted adipocyte differentiation by upregulating key adipogenic markers (PPARγ, Adiponectin, C/EBPα, and FABP4). In contrast, gene silencing enhanced the proliferative capacity and decreased lipid droplet accumulation, confirming its inhibitory role in adipogenesis. Our findings indicate that FGFBP1 is a key regulator of tail adipogenesis. This discovery enhances our understanding of the mechanisms of adipocyte differentiation and provides theoretical bases and potential therapeutic targets for optimizing lipid deposition traits in livestock production. Full article

Dynamin-related protein 1 (Drp1) is a crucial player in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are fundamental for lipid metabolism. This study utilized liver-specific Drp1 knockout (Drp1LiKO) mice to investigate the effects of Drp1 deficiency on organelle interactions, metabolism, and inflammation. Our analysis revealed disrupted interactions between mitochondria and LDs, as well as altered interactions among ER, mitochondria, and LDs in Drp1LiKO mice. Through mass spectrometry and microarray analysis, we identified changes in lipid profiles and perturbed expression of lipid metabolism genes in the livers of Drp1LiKO mice. Further in vitro experiments using primary hepatocytes from Drp1LiKO mice confirmed disturbances in lipid metabolism and increased inflammation. These findings highlight the critical involvement of Drp1 in regulating organelle interactions for efficient lipid metabolism and overall liver health. Targeting Drp1-mediated organelle interactions may offer potential for developing therapies for liver diseases associated with disrupted lipid metabolism. Full article

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, and it is characterized by oxidative stress, lipid dysregulation, and dysfunction of the retinal pigment epithelium (RPE). A hallmark of AMD is the presence of drusen, extracellular deposits rich in lipids, proteins, and cellular debris, which are secreted by the RPE. These deposits impair RPE function, promote chronic inflammation, and accelerate disease progression. Despite advancements in understanding AMD pathogenesis, therapeutic strategies targeting lipid dysregulation and oxidative damage in RPE cells remain limited. This study evaluated the effects of liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), on free fatty acid (FFA)-induced damage in ARPE-19 cells, a widely used in vitro model of RPE dysfunction. FFA treatment induced lipid droplet accumulation, oxidative stress, and epithelial–mesenchymal transition (EMT), which are processes implicated in AMD progression. Liraglutide significantly reduced lipid droplet accumulation, mitigated oxidative stress, and suppressed EMT, as demonstrated by high-content imaging, immunocytochemistry, and molecular assays. Mechanistic analyses revealed that liraglutide activates AMP-activated protein kinase (AMPK), enhancing lipophagy and restoring lipid homeostasis. Furthermore, liraglutide influenced exosome secretion, altering paracrine signaling and reducing EMT markers in neighboring cells. These findings underscore liraglutide’s potential to address critical mechanisms underlying AMD pathogenesis, including lipid dysregulation, oxidative stress, and EMT. This study provides foundational evidence supporting the development of GLP-1 receptor agonists as targeted therapies for AMD. Full article

Intramuscular fat (IMF) content is a key factor influencing meat properties including tenderness, flavor, and marbling. However, the complex molecular mechanisms regulating IMF deposition, especially the interactions between intramuscular preadipocytes (IMAdCs) and skeletal muscle satellite cells (SMSCs), remain unclear. In this study, a direct co-culture system of sheep IMAdCs and SMSCs was used to elucidate their intercellular interactions. RNA sequencing and bioinformatics analyses were performed under monoculture and co-culture conditions for later stages of differentiation. The obtained results showed that SMSCs significantly inhibited the adipogenic capacity of IMAdCs. This was reflected in the co-culture markedly altered gene expression and observations of lipid droplets in our studies, i.e., the PPARG, ACOX2, PIK3R1, FABP5, FYN, ALDOC, PFKM, PFKL, HADH, and HADHB genes were down-regulated in the co-cultured IMAdCs in association with the inhibition of fat deposition, whereas ACSL3, ACSL4, ATF3, EGR1, and IGF1R within the genes upregulated in co-culture IMAdCs were associated with the promotion of lipid metabolism. In addition, GO, KEGG, and ligand–receptor pairing analyses further elucidated the molecular mechanisms of intercellular communication. These findings emphasize the regulatory role of SMSCs on intramuscular preadipocyte differentiation and lipid metabolism, providing a theoretical framework for targeted molecular strategies to improve sheep meat quality. Full article