Altered Lipid Metabolism Research Articles

Reshaping lipid metabolism with long-term alternate day feeding in type 2 diabetes mice

Strategies to improve metabolic health include calorie restriction, time restricted eating and fasting several days per week or month. These approaches have demonstrated benefits for individuals experiencing obesity, metabolic syndrome, and prediabetes. However, their impact on established diabetes remains incompletely studied. The chronicity of type 2 diabetes (T2D) requires that interventions must be undertaken for extended periods of time, typically the entire lifetime of the individual. In this study, we examined the impact of intermittent fasting (IF), with an every-other-day protocol for a duration of 6 months in a murine model of T2D, the db/db (D) mouse on metabolism and liver steatosis. We compared D-IF mice with diabetic ad-libitum (AL; D-AL), control-IF (C-IF) and control-AL (C-AL) cohorts. We demonstrated using lipidomic, microbiome, metabolomic and liver transcriptomic studies that chronic IF improved carbohydrate utilization and glucose homeostasis without weight loss and reduced white adipose tissue inflammation and significantly impacted lipid metabolism in the liver. Microbiome studies and predicted functional analysis of gut microbiota showed that IF increased beneficial bacteria involved in sphingolipid (SL) metabolism. The metabolomic studies showed that oxidation of lipid species and ceramide levels were reduced in D-IF compared to D-AL. The liver lipidomic analysis and liver microarray confirmed a reduction in overall lipid content in D-IF mice compared to D-AL mice, especially in the feeding state as well as an overall reduction in oxidized lipids and ceramides. These studies support that long-term IF can improve glucose homeostasis and dramatically altered lipid metabolism in the absence of weight loss.

Radiosensitizing Capacity of Fenofibrate in Glioblastoma Cells Depends on Lipid Metabolism

Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby contributes to radioresistance in GBM, is a hallmark of cancer. Therefore, we explored the radiosensitizing effect of the clinically approved, lipid-lowering drug fenofibrate (FF) in different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress and impairing mitochondrial membrane integrity, but radioprotects LN18 cells by reducing the production of reactive oxygen species (ROS) and stabilizing the mitochondrial membrane potential. A comparative protein and lipid analysis revealed striking differences in the two GBM cell lines: LN18 cells exhibited a significantly higher membrane expression density of the fatty acid (FA) cluster protein transporter CD36 than U87 cells, a higher expression of glycerol-3-phosphate acyltransferase 4 (GPAT4) which supports the production of large lipid droplets (LDs), and a lower expression of diacylglycerol O-acyltransferase 1 (DGAT1) which regulates the formation of small LDs. Consequently, large LDs are predominantly found in LN18 cells, whereas small LDs are found in U87 cells. After a combined treatment of FF and irradiation, the number of large LDs significantly increased in radioresistant LN18 cells, whereas the number of small LDs decreased in radiosensitive U87 cells. The radioprotective effect of FF in LN18 cells could be associated with the presence of large LDs, which act as a sink for the lipophilic drug FF. To prevent uptake of FF by large LDs and to ameliorate its function as a radiosensitizer, FF was encapsulated in biomimetic cell membrane extracellular lipid vesicles (CmEVs) which alter the intracellular trafficking of the drug. In contrast to the free drug, CmEV-encapsulated FF was predominantly enriched in the lysosomal compartment, causing necrosis by impairing lysosomal membrane integrity. Since the stability of plasma and lysosomal membranes is maintained by the presence of the stress-inducible heat shock protein 70 (Hsp70) which has a strong affinity to tumor-specific glycosphingolipids, necrosis occurs predominantly in LN18 cells having a lower membrane Hsp70 expression density than U87 cells.In summary, our findings indicate that the lipid metabolism of tumor cells can affect the radiosensitizing capacity of FF when encountered either as a free drug or as a drug loaded in biomimetic lipid vesicles.

ECM-mimicking hydrogel models of human adipose tissue identify deregulated lipid metabolism in the prostate cancer-adipocyte crosstalk under antiandrogen therapy.

Antiandrogen therapies are effectively used to treat advanced prostate cancer, but eventually cancer adaptation drives unresolved metastatic castration-resistant prostate cancer (mCRPC). Adipose tissue influences metabolic reprogramming in cancer and was proposed as a contributor to therapy resistance. Using extracellular matrix (ECM)-mimicking hydrogel coculture models of human adipocytes and prostate cancer cells, we show that adipocytes from subcutaneous or bone marrow fat have dissimilar responses under the antiandrogen Enzalutamide. We demonstrate that androgen receptor (AR)-dependent cancer cells (LNCaP) are more influenced by human adipocytes than AR-independent cells (C4-2B), with altered lipid metabolism and adipokine secretion. This response changes under Enzalutamide, with increased AR expression and adipogenic and lipogenic genes in cancer cells and decreased lipid content and gene dysregulation associated with insulin resistance in adipocytes. This is in line with the metabolic syndrome that men with mCRPC under Enzalutamide experience. The all-human, all-3D, models presented here provide a significant advance to dissect the role of fat in therapy response for mCRPC.

Role of miR-125b-5p in modulating placental SIRT7 expression and its implications for lipid metabolism in gestational diabetes.

Gestational diabetes is marked impaired glucose tolerance, poses various adverse outcomes including increased BMI and obesity. These outcomes results from excess lipid accumulation which is marked by elevated triglycerides. In GDM, placenta exhibits altered lipid metabolism, including reduced fatty acid oxidation and increased triglyceride accumulation. These elevated triglycerides can also contribute to oxidative stress in GDM. SIRT7 plays an important role in regulating lipid metabolism and triglycerides levels. This study aimed to investigate the potential of miRNA to regulate the placental SIRT7 in GDM. PCR analysis reveals that SIRT7 expression along with oxidative stress markers elevated in GDM placenta. These elevated SIRT7 levels were positively correlated with BMI and triglycerides levels in GDM subjects. miR-125b-5p was identified to regulate SIRT7 mRNA using in-silico approaches. Expression levels of miR-125b-5p were found to be downregulated in GDM placenta and found to be negatively correlated with SIRT7 mRNA expression. To confirm the hypothesis BeWo cells were transfected with anti-miR-125b and miR-125b-mimic. Anti-miR overexpressed the SIRT7 expression where mimic dysregulated it. Additionally, overexpressing miR-125b-5p controlled the elevated SIRT7 caused by the exposure of high glucose in BeWo cells. Collectively this study indicated that miR-125b-5p may regulate lipid metabolism via SIRT7 contributing to GDM. These findings highlights the warrant of further research to develop the therapeutic approaches that target miR-125b-5p to reduce lipid accumulation and obesity in GDM.

Differential transcriptomic profiling of lipid metabolism and collagen remodeling in fast- and slow-twitch skeletal muscles in aging.

Skeletal muscle function gradually declines with aging, presenting substantial health and societal challenges. Comparative analysis of how aging affects fast- and slow-twitch muscles remains lacking. We utilized 20-month-old mice to reveal the aging effects on muscle structure and fiber composition, followed by bulk RNA sequencing for fast- and slow-twitch muscles and integration with human single-cell RNA sequencing dataset providing a comparative analysis across species. In mouse slow-twitch muscles, aging induced a switch from fast to slow fibers and distinctively altered lipid metabolism in ceramide and triglyceride, with the upregulation of regulatory genes Gk and Ppargc1a also observed in human slow fibers. Additionally, both types of muscles exhibited common collagen deposition and fibrosis, possibly due to the imbalance between collagen synthesis and degradation. The extracellular matrix gene changes substantially overlapped between mice and humans in aging, yet also highlighted clear differences. This integrative analysis provides further understanding of aged fast- and slow-twitch muscles and offers new insights into the molecular changes in aging.

Effect of laparoscopic cholecystectomy on plasma levels of EETs, arachidonic acids derived lipid mediators.

Epoxyeicosatrienoic acids (EETs) are closely associated with lipoprotein metabolism, and changes in lipid profiles potentially affect their levels and functions. Given the alterations in lipid metabolism after cholecystectomy, this study aimed to investigate the levels of four EET regioisomers (free and esterified) and lipid profiles in patients with cholelithiasis after laparoscopic cholecystectomy (LC) and explore correlations between these parameters. This prospective study involved 40 patients with symptomatic cholelithiasis who underwent LC. Plasma EETs and serum total cholesterol, triglyceride, high-density lipoprotein (HDL), very low-density lipoprotein, low-density lipoprotein, and body mass index (BMI) values were determined preoperatively and after 6 months of LC. After LC, triglyceride and very low-density lipoprotein levels increased while TC decreased. BMI values increased significantly after the operation. Despite plasma EET levels decreasing remarkably after surgery, this change did not reach statistical significance. A significant correlation was observed between preoperative levels of 8,9- and 11,12-EET and pre-and post-operative HDL. There was a significant negative correlation between the EET levels measured before and after surgery and the change in BMI values. In this study, we observed significant changes in lipid profile 6 months after LC. While HDL, low-density lipoprotein, and EET levels showed a decreasing trend post-surgery, this change was not statistically significant. This trend and their significant correlations may indicate a complex relationship between HDL and EET metabolism. In addition, the negative correlation between EET levels and BMI changes highlights the need for further research to elucidate the metabolic impact and weight regulation of EETs after LC.

DLAT is involved in ovarian cancer progression by modulating lipid metabolism through the JAK2/STAT5A/SREBP1 signaling pathway

BackgroundOvarian cancer (OC) remains a lethal gynecological malignancy with an alarming mortality rate, primarily attributed to delayed diagnosis and a lack of effective treatment modalities. Accumulated evidence highlights the pivotal role of reprogrammed lipid metabolism in fueling OC progression, however, the intricate underlying molecular mechanisms are not fully elucidated.MethodsDLAT expression was assessed in OC tissues and cell lines by immunohistochemistry, western blot and qRT-PCR analysis. The effects of DLAT silencing on changes in lipid metabolism, cell viability, migration, and invasion were examined in SKOV3 and OVCAR3 cells using CCK-8, colony formation, Transwell migration and invasion, and wound-healing assays. GSEA analysis was used to examine the relationship between DLAT and lipid metabolism-related enzymes. Rescue experiments in which SREBP1 was overexpressed in DLAT-silenced cells were carried out. Western blot analysis was performed to determine whether the JAK2/STAT5 signaling pathway was involved in DLAT-regulated SREBP1 expression. Commercially available triglyceride and cholesterol detection kits, as well as Nile Red and Oil red O staining were used to measure lipid metabolism. A subcutaneous tumor model was established in BALB/c mice to confirm the role of the DLAT/SREBP1 axis in OC growth and metastasis in vivo.ResultsDLAT expression was significantly upregulated in OC patient tissue and associated with poor prognosis. Silencing DLAT reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression via the JAK2/STAT5 signaling pathway, enhancing expression of fatty acid synthesis enzymes and altering lipid metabolism. SREBP1 was essential for DLAT-dependent OC cell growth and metastasis both in vitro and in vivo.ConclusionThis study uncovers a novel DLAT/JAK2/STAT5/SREBP1 axis that reprograms lipid metabolism in OC, providing insights into metabolic vulnerabilities and potential therapeutic targets for OC treatment.

Glo1 reduction in mice results in age- and sex-dependent metabolic dysfunction.

Advanced glycation end products (AGEs) have been implicated as an important mediator of metabolic disorders including obesity, insulin resistance, and coronary artery disease. Glyoxalase 1 (Glo1) is a critical enzyme in the clearance of toxic dicarbonyl such as methylglyoxal, precursors of AGEs. The role of AGE-independent mechanisms that underly Glo1-induced metabolic disorders have yet to be elucidated. We performed a longitudinal study of female and male Glo1 heterozygous knockdown ( Glo1 +/- ) mice with ∼50% gene expression and screened metabolic phenotypes such as body weight, adiposity, glycemic control and plasma lipids. We also evaluated atherosclerotic burden, AGE levels, and gene expression profiles across cardiometabolic tissues (liver, adipose, muscle, kidney and aorta) to identify pathway perturbations and potential regulatory genes of Glo1 actions. Partial loss of Glo1 resulted in obesity, hyperglycemia, dyslipidemia, and alterations in lipid metabolism in metabolic tissues in an age- and sex-dependent manner. Glo1 +/- females displayed altered glycemic control and increased plasma triglycerides, which aligned with significant perturbations in genes involved in adipogenesis, PPARg, insulin signaling, and fatty acid metabolism pathways in liver and adipose tissues. Conversely, Glo1 +/- males developed increased skeletal muscle mass and visceral adipose depots along with changes in lipid metabolism pathways. For both cohorts, most phenotypes manifested after 14 weeks of age. Evaluation of methylglyoxal-derived AGEs demonstrated changes in only male skeletal muscle but not in female tissues, which cannot explain the broad metabolic changes observed in Glo1 +/- mice. Transcriptional profiles suggest that altered glucose and lipid metabolism may be partially explained by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Moreover, transcription factor (TF) analysis of the tissue-specific gene expression data identified TFs involved in cardiometabolic diseases such as Hnf4a (all tissues) and Arntl (aorta, liver, and kidney) which are female-biased regulators and whose targets are altered in response to Glo1 +/- . Our results indicate that Glo1 reduction perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without significant changes in AGEs across metabolic tissues. Rather, tissue-specific gene expression analysis suggests that key transcription factors such as Hfn4a and Arntl as well as metabolite changes from alternative methylglyoxal detoxification such as pyruvate, likely contribute to metabolic dysregulation in Glo1 +/- mice.

P0565 Spatial Metabolic Profiles in Ulcerative colitis patients determine response to therapy

Abstract Background Ulcerative Colitis (UC) is an heterogenous debilitating disease without a cure. The step-up therapy approach aims at controlling and alleviating intestinal inflammation by achieving and maintaining clinical and endoscopic remission. However, the rate of primary non-response or loss of response to therapies is still high. Predictive markers that accurately guide decisions about the best therapeutic choice are an unmet need. This study aims to determine the intestinal metabolic profiles of UC patients and explore differences in response groups of given treatments, thus helping a better patient stratification. Methods Mucosal biopsies collected from active UC patients (N=26) at week 0 and 14 after treatment (vedolizumab, tofacitinib and filgotinib) were sectioned at 10 µm thickness. Patients were classified as non-responders (NR), responders (R) and super responders (SR) based on both endoscopic and partial Mayo scores. Sections were processed by matrix-assisted laser desorption/ionization (MALDI) coupled with Orbitrap Exploris™ 120 Mass Spectrometer. Raw spectral data was processed with MSConverter and MSIpixel for metabolite quantification and annotation. Comprehensive statistical analyses including quantitative metabolite distributions, Moran’s I spatial correlations and pathway enrichment analysis were performed via an in-house developed computational pipeline. Results Spatial metabolomic analysis revealed different metabolite patterns between R and NR across all drugs. Notably, all non-responders exhibited a dysregulated lipid metabolism. In the Vedolizumab group, a fragmented pattern distribution of metabolites was found in NR characterized by an increase of canavalmine, N1-acetylspermidine and heptanenitrile at week 0, whereas SR showed a significant tissue reorganization environment, with increased number of metabolites such as LysoPA, LysoPE and 5alpha-Cholesta-7,24dien-3beta-ol, involved in anti-inflammatory pathways, as well as glutathione and purine metabolism. Additionally, SR showed histamine- and IgE-related pathways supporting cellular regeneration. Conclusion Overall, these data depicted the alteration of mucosal lipid metabolism as a hallmark of non-response to therapies, and evidenced that the effectiveness of a specific treatment in UC is impacted by the initial mucosal metabolic state conditioned by diet and medications. The validation of these results in a larger sample size will aid the prediction of therapy response. References ImmUniverse project: this project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 853995. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The content provided in this abstract reflects only the author's view and neither the IMI JU nor the European Commission are responsible for any use that may be made of the information it contains.

Synergistic Assessment of Supplementation of Ascorbic Acid and Massularia acuminata Extracts on Serum Electrolyte and Lipid Profile Indices of Dyslipidemia in Adult Wistar Rats Exposed to Aluminum Chloride Toxicity

Background: Aluminum chloride (AlCl3) toxicity is a growing concern due to its prevalence usage in various industrial and environmental settings. Prolonged exposure to aluminum chloride can lead to oxidative stress, electrolyte imbalances, and alterations in lipid metabolism. This study aimed to investigate the effects of supplementation of ascorbic acid and Massularia acuminata extracts on electrolyte function and lipid profile parameters in adult Wistar rats exposed to aluminum chloride toxicity. Methodology: The stem barks of Massularia acuminata were air-dried at room temperature for thirty (30) days and were mechanically ground into fine powder by using an electrical mill. The powder was kept in air-tight container until use. Six hundred (600 g) of the dried powders was dissolved in 4 litres of 80 % (v/v) of methanol, ethanol and butanol respectively for 72 h with occasional agitation using sterile rod. The resulting mixture obtained was then filtered using pieces of white cotton gauze and concentrated in a rotary evaporator following by dryness under vacuo at 40 0C in a rotary evaporator. The extracts that were obtained were then concentrated to dryness ‘in vacuo’ to yield the respective solvent extracts For the animal study, then, fifty Adult Wistar rats was randomly divided into several groups, including a control group, an aluminum chloride-exposed group, and treatment groups supplemented with ascorbic acid, Massularia acuminata extracts, and combination of both in varied doses. The dosage of supplementation was determined based on preliminary experiments and relevant literature. The rats in the aluminum chloride-exposed group and the treatment groups received oral administration of aluminum chloride at a specific dose of (34 mg/kg) for a defined duration to induce toxicity. The control group received a placebo. The treatment groups received supplementation of Ascorbic Acid and Massularia acuminata extracts received daily oral supplementation of ascorbic acid, Massularia acuminata extracts, or a combination of both, while the control and aluminum chloride-exposed groups received a placebo. Results: The result showed that there was a significant (p &lt; 0.05) decrease in the lipid profile of Total Cholesterol (TC), Very Low-Density Lipoprotein (VLDL) and a non-significant decrease in High Density Lipoprotein (HDL) treated with vitamin C while a significant decrease in the level of HDL, VLDL, LDL and cholesterol were observed from the groups treated with the various plant extracts. Conclusion: From the study, it can therefore be concluded that ethanol leaf extract of Massularia acuminata has protective effect against aluminium chloride induced hepatotoxicity, oxidative stress and alterations in lipid and electrolyte profile in Wistar rats.

Cardiovascular Risk Factor and Atherosclerosis in Rheumatoid Arthritis (RA).

To highlight advancements in managing traditional and rheumatoid arthritis (RA) specific risk factors and the impact of RA treatments on cardiovascular outcomes. Advancements in rheumatoid arthritis management have paralleled declining trends in cardiovascular disease risks. Biomarkers like CRP, Lipoprotein(a), Apolipoprotein B 100, and imaging tools such as coronary artery calcium scoring enhance cardiovascular risk stratification, particularly in intermediate-risk RA patients. While effective RA treatments, have demonstrated substantial cardiovascular benefits, subclass differences were noted in high-risk patients. Increased risk of cardiovascular disease is driven by chronic inflammation, altered lipid metabolism, and traditional risk factors. Effective RA treatment significantly lowers cardiovascular events. Standard treatment of hypertension, diabetes and hypercholesterolemia are effective and lowers RA disease activity and inflammatory markers. While RA is considered a risk enhancing state in calculating CV risk scores, currently there exists no RA disease -specific blood pressure, blood sugar or lipid targets.

Mitochondrial quality control: Biochemical mechanism of cardiovascular disease.

Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.

Hypoxia and lipid metabolism related genes drive proliferation migration and immune infiltration mechanisms in colorectal cancer subtyping

Hypoxia and lipid metabolism play crucial roles in the progression of colorectal cancer (CRC). However, the specific functions of hypoxia- and lipid metabolism-related genes (HLPG) in CRC and their relationships with patient prognosis remain unclear. Differential expression analysis using the TCGA-COAD and GEO databases identified 117 HLPGs through the intersection of the two gene sets. After univariate Cox regression analysis, 17 prognostically relevant HLPG were identified. Consensus clustering classified CRC samples into two subtypes, and the immune microenvironment differences between them were evaluated. A risk scoring model utilizing seven prognostically significant HLPGs was created and its predictive performance was assessed through survival analysis and ROC curves. Finally, the key genes ITLN1 and SFRP2 were functionally validated in CRC cell lines. HLPG was closely linked to CRC prognosis. Two molecular subtypes were identified: Cluster A, characterized by enriched immune pathways and higher immune infiltration, and Cluster B, associated with improved overall survival. The seven HLPG-based risk scoring model effectively stratified patients into high- and low-risk groups, with high-risk patients exhibiting significantly poorer survival outcomes. Functional studies confirmed that SFRP2 and ITLN1 play essential roles in CRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, ITLN1 upregulated PD-L1 expression, increasing sensitivity to immunotherapy. Hypoxia was found to promote lipid metabolic alterations by modulating SFRP2 and ITLN1 expression. This study highlights the prognostic significance of HLPGs in CRC and introduces a robust risk scoring model for patient outcome prediction. ITLN1 could be a target for enhancing immunotherapy response in CRC.

Eating behavior patterns, metabolic parameters and circulating oxytocin levels in patients with obesity: an exploratory study

PurposeObesity is a complex heterogeneous disease often associated with dysfunctional eating behavior patterns. Oxytocin (OT) is a neurohormone involved in the regulation of energy metabolism and eating behavior. The aim of the present study was to evaluate in a population of patients with obesity circulating levels of OT and dysfunctional eating behaviors in relation to anthropometric, hormonal and metabolic parameters.MethodsA prospective, observational, single-center study was conducted at the Center of High Specialization for the Care of Obesity of Sapienza University of Rome. Adult subjects with body mass index (BMI) ≥ 30 kg/m2 were recruited. Body impedance assessment (BIA), biochemical and hormonal parameters, plasma OT concentration analysis and the Eating Behaviors Assessment for Obesity (EBA-O) questionnaire were evaluated.ResultsA total of 21 patients, 16 females and 5 males, with a mean age of 45.7 ± 15.1 years, mean BMI of 40.89 ± 8.02 kg/m2 and plasma OT concentration of 1365.61 ± 438.03 pg/mL were recruited. The dysfunctional eating behavior traits investigated by the EBA-O appear significantly associated with metabolic derangements. In particular, night eating is associated with alterations in lipid metabolism (p < 0.01). Circulating OT correlates positively with BMI (r = 0,43; p < 0.05), and Hepatic Steatosis Index (HIS) (r = 0.46; p < 0.05), while its role in subjects with obesity and alterations in glucose metabolism is less clear. Interestingly, circulating OT levels < 1312.55 pg/mL may be predictive of food addiction (100% sensitivity; 62.5% specificity).ConclusionsDespite the need for larger studies to confirm their validity, the clinical utility of the EBA-O and circulating OT in identifying dysfunctional eating behaviors appears promising.

Lipid Metabolism Alterations in Hyperlipidemic Dogs with Biliary Tract or Endocrine Diseases.

Fasting hyperlipidemia results from lipid metabolism defects associated with alterations in specific lipoprotein classes. These changes may originate from genetic predispositions or underlying metabolic disorders, including cholestasis and endocrine diseases. This retrospective study aimed to analyze variations in lipoprotein electrophoresis (LPE) profiles in hyperlipidemic dogs and investigate the associations between biliary tract diseases, endocrine disorders, and lipid metabolism. Sixty-five dogs that underwent LPE were classified into non-hyperlipidemic (NHL) and hyperlipidemic (HL) groups, with further subdivisions based on the presence of biliary tract disease, endocrine disorders, or breed predisposition (Miniature Schnauzers). Dogs in the HL group with biliary tract disease and those with underlying metabolic disorders exhibited significantly higher pre-beta fractions and cholesterol concentrations compared to the NHL group. Additionally, significant linear relationships were observed between serum gamma-glutamyl transpeptidase (GGT) levels and both pre-beta fractions and cholesterol concentrations. The Schnauzer group showed lower alpha fractions and higher triglyceride and cholesterol levels than the NHL group. These findings suggest that LPE is a valuable and useful tool for detecting lipid metabolism abnormalities. Clinicians should consider the potential for altered lipid metabolism when evaluating patients with biliary tract or endocrine diseases in small animal practice.

Treating Metabolic Dysregulation and Senescence by Caloric Restriction: Killing Two Birds with One Stone?

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth factor signaling (IIS), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase. The dysregulation of these pathways contributes to insulin resistance, impaired autophagy, exacerbated oxidative stress, and mitochondrial dysfunction, further enhancing cellular senescence and systemic metabolic derangements. On the other hand, dysfunctional endothelial cells and adipocytes contribute to systemic inflammation, reduced nitric oxide production, and altered lipid metabolism. Numerous factors, including extracellular vesicles, mediate pathological communication between the vascular system and adipose tissue, amplifying metabolic imbalances. Meanwhile, caloric restriction (CR) emerges as a potent intervention to counteract overnutrition effects, improve mitochondrial function, reduce oxidative stress, and restore metabolic balance. CR modulates pathways such as IIS, mTOR, and sirtuins, enhancing glucose and lipid metabolism, reducing inflammation, and promoting autophagy. CR can extend the health span and mitigate age-related diseases by delaying cellular senescence and improving healthy endothelial-adipocyte interactions. This review highlights the crosstalk between endothelial cells and adipocytes, emphasizing CR potential in counteracting overnutrition-induced senescence and restoring vascular homeostasis.

In Utero Perfluorodecanoic Acid Exposure Causes Fetal Leydig Cell Dysfunction via Endoplasmic Reticulum Stress-Mediated Lipid Composition Alteration.

Perfluorodecanoic acid (PFDA), a C10 fluorine-containing compound, is used widely and found to be present anywhere. However, whether it has reproductive toxicity for fetal Leydig cells and the underlying mechanisms remain unknown. PFDA was investigated for its effects on fetal Leydig cells (FLCs) following exposure to 0, 1, 2.5, and 5 mg/kg/days (gavage to dams) from day 14 to day 21 during gestation. The study showed that in utero medium-dose PFDA (1, 2.5 mg/kg/days) exposure increased fetal body weight. However, PFDA markedly reduced serum testosterone levels, downregulated FLC genes (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Insl3), and decreased their protein levels in neonatal rat testes. PFDA at 5 mg/kg/day altered lipid metabolism with upregulation of Elovl1 and downregulation of Scd2, subsequently inducing endoplasmic reticulum stress. Additionally, PFDA exposure downregulated transcription factor Gli1, thereby inhibiting fetal Leydig cell differentiation. Meanwhile, PFDA reduced testosterone biosynthesis in R2C Leydig cells in vitro, and the endoplasmic reticulum stress inhibitor tauroursodeoxycholic acid (TUDCA) reversed this process. In conclusion, PFDA disrupts fetal rat testicular lipid metabolism, induces endoplasmic reticulum stress, and interferes with the steroidogenesis network, leading to fetal Leydig cell dysfunction. This study underscores the potential environmental risk of PFDA exposure on the development of male reproductive function development.

Precision fetal cardiology detects cyanotic congenital heart disease using maternal saliva metabolome and artificial intelligence

Prenatal sonographic diagnosis of congenital heart disease (CHD) can lead to improved morbidity and mortality. However, the diagnostic accuracy of ultrasound, the sole prenatal screening tool, remains limited. Failed prenatal or early newborn detection of cyanotic CHD (CCHD) can have disastrous consequences. We therefore sought to use a Precision Fetal Cardiology based approach combining metabolomic profiling of maternal saliva and machine learning, a major branch of artificial intelligence (AI), for the prenatal detection of isolated, non-syndromic cyanotic CHD. Metabolomic analyses using Ultra-High Performance Liquid Chromatography/Mass Spectrometry identified 468 metabolites in the saliva. Six different AI platforms were utilized for the detection of CCHD and CHD overall. AI achieved excellent accuracy for the CCHD detection: Area Under the ROC curve: AUC (95% CI) = 0.819 (0.635-1.00) with a sensitivity and specificity of 92.5% and 87.0%, and for CHD overall: AUC (95% CI) = 0.828 (0.635-1.00) with a sensitivity of 90.5% and specificity of 88.0%. Similarly high accuracies were achieved for the detection of CHD overall: AUC (95% CI) = 0.8488 (0.635-1.00) with a sensitivity of 92.5% and specificity of 91.0%. Pathway analysis showed significant alterations in Arachidonic Acid, Alpha-linoleic acid, and Tryptophan metabolism indicating significant lipid dysfunction in cyanotic CHD. In summary, we report for the first time, the accurate detection of non-syndromic cyanotic CHD using maternal salivary metabolomics. Further, analysis revealed significant alteration of lipid metabolism.

Degenerated vision, altered lipid metabolism, and expanded chemoreceptor repertoires enable Lindaspio polybranchiata to thrive in deep-sea cold seeps

BackgroundLindaspio polybranchiata, a member of the Spionidae family, has been reported at the Lingshui Cold Seep, where it formed a dense population around this nascent methane vent. We sequenced and assembled the genome of L. polybranchiata and performed comparative genomic analyses to investigate the genetic basis of adaptation to the deep sea. Supporting this, transcriptomic and fatty acid data further corroborate our findings.ResultsWe report the first genome of a deep-sea spionid, L. polybranchiata. Over long-term adaptive evolution, genes associated with vision and biological rhythmicity were lost, which may indirectly benefit oligotrophy by eliminating energetically costly processes. Compared to its shallow-sea relatives, L. polybranchiata has a significantly higher proportion of polyunsaturated fatty acids (PUFAs) and expanded gene families involved in the biosynthesis of unsaturated fatty acids and chromatin stabilization, possibly in response to high hydrostatic pressure. Additionally, L. polybranchiata has broad digestive scope, allowing it to fully utilize the limited food resources in the deep sea to sustain a large population. As a pioneer species, L. polybranchiata has an expanded repertoire of genes encoding potential chemoreceptor proteins, including ionotropic receptors (IRs) and gustatory receptor-like receptors (GRLs). These proteins, characterized by their conserved 3D structures, may enhance the organism’s ability to detect chemical cues in chemosynthetic ecosystems, facilitating rapid settlement in suitable environments.ConclusionsOur results shed light on the adaptation of Lindaspio to the darkness, high hydrostatic pressure, and food deprivation in the deep sea, providing insights into the molecular basis for L. polybranchiata becoming a pioneer species.

Neonatal Circulating Amino Acids and Lipid Metabolites Mediate the Association of Maternal Gestational Diabetes Mellitus with Offspring Neurodevelopment at 1 Year.

Background/Objectives: We aimed to identify neonatal circulating metabolic alterations associated with maternal gestational diabetes mellitus (GDM) and to explore whether these altered metabolites could mediate the association of GDM with offspring neurodevelopment. Additionally, we investigated whether neonatal circulating metabolites could improve the prediction of offspring neurodevelopmental disorders over traditional risk factors. Methods: The retrospective cohort study enrolled 1228 mother-child dyads in South China. GDM was diagnosed at 24-28 weeks of gestation. Neonatal circulating amino acids and lipid metabolites (carnitines) were measured from newborn heel blood 3-7 days postpartum. Offspring neurodevelopment was assessed at age 1 year using the Children Neuropsychological and Behavioral Examination Scale. Neurodevelopmental disorders were defined as developmental delay in any domain of the scale. Results: Twenty-one metabolites associated with GDM were identified, consisting of seven amino acids and fourteen carnitines. Among these metabolites, five (glycine, myristicylcarnitine, palmitoylcarnitine, octadecadienoylcarnitine, and 3-hydroxypalmitylcarnitine) mediated the negative association of GDM with offspring neurodevelopment at 1 year (mediation proportions: 3.91-10.66%). Furthermore, six metabolites (glycine, methionine, malonylcarnitine, isovalerylcarnitine, palmitoylcarnitine, and octadecadienoylcarnitine) significantly increased the predictive performance for offspring neurodevelopmental disorders at 1 year over five traditional risk factors including GDM, parity, infant sex, birth weight, and feeding patterns (area under curve: 0.762 vs. 0.718, p = 0.012). Conclusions: GDM was associated with a variety of amino acid and lipid metabolic alterations in neonatal circulation, among which certain metabolites mediated the association of GDM with adverse neurodevelopmental outcomes in offspring. Moreover, some neonatal circulating metabolites may serve as potential biomarkers that improved the prediction of offspring neurodevelopmental disorders over GDM and other traditional risk factors.