Lipid Metabolism Research Articles

Metabolic disruption by mycotoxins: focus on metabolic endpoints steatosis, adipogenesis and glucose metabolism in vivo and in vitro.

Metabolic disruption encompasses the processes leading to adverse effects to major metabolic organs, such as liver and pancreas after exposure to e.g., environmental chemicals. As some mycotoxins act as endocrine disruptors, their structural similarity may lead to effects in lipid and glucose metabolism as well. Via systematic literature search, we mapped the potential of mycotoxins to cause metabolic disruption. Our systematic data search involved mycotoxin keywords combined with metabolic disruption keywords. The retrieved 31 studies revealed 24 in vivo studies, and 18 in vitro studies in total of 13 different mycotoxins. Most studied parameters were triglycerides from blood or liver, followed by total cholesterol and glucose or insulin levels. In vitro studies most often aimed to reveal mechanisms of metabolic disruption, but common metabolic parameters (lipid or cholesterol accumulation). In general, mycotoxin exposure showed a trend towards positive metabolic effects, such as reduction of blood triglycerides levels. Emodin was the most studied mycotoxin. Other mycotoxins were studied in one to three studies. Positive effects were also identified for equisetin, fumonisin B1, fumigaclavine C and ergostatrien-3-B-ol. Adverse effects (e.g. increased lipid deposition to liver) were identified for aflatoxin B1, ochratoxin A, deoxynivalenol, citreoviridin, T-2 toxin and paxilline. As demonstrated by the evaluated in vivo and in vitro studies, mycotoxins seem to have more positive than negative effects on metabolism. However, based on the available data, a general conclusion on the role of mycotoxins as a group cannot be made.

Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk

BackgroundThe liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.MethodsLarge-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10−8) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.ResultsMR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03–1.18, P = 4.23 × 10⁻3) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03–1.17, P = 3.28 × 10⁻3) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.ConclusionsHigher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.

ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism

BackgroundProstate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown.MethodsWe performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells.ResultsANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate.ConclusionsThis study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7’s biology.

Genome-wide association study of the fatty liver index in the Taiwanese population reveals shared and population-specific genetic risk factors across ethnicities

Background and objectivesAlthough the incidence of fatty liver disease (FLD) is increasing worldwide, the genetic basis of this disease is not fully understood. This study uses the fatty liver index (FLI) to identify and compare genetic variants associated with FLD in Taiwanese and European populations.ResultsIn this study, a total of 145,356 Taiwan Biobank participants were included in the discovery analysis. Subjects with elevated FLI were found to have a significantly greater risk of developing FLD, as confirmed by imaging data (OR: 4.43; 95% CI: 3.88–5.06). Through genome-wide association studies (GWAS), we identified 6 variants previously associated with nonalcoholic fatty liver disease (NAFLD) and validated 50 shared risk variants located in ZPR1 and FTO between the Taiwanese and European populations. Conditional analysis of 423 significant variants from FLI-defined FLD further revealed 16 independent variants within 14 genes. Pathway analysis of GWAS significant genes revealed that lipid metabolism and the peroxisome proliferator-activated receptor (PPAR) signaling pathway are causes of hepatic fat accumulation.ConclusionThis study identified six independent NAFLD-associated variants in GCKR, LPL, TRIB1AL, and FTO and emphasized ZPR1 and FTO as shared risk genes for FLI-defined FLD in both Taiwanese and European populations. These findings support the utility of the FLI for FLD prediction, provide new genetic insights, and reveal the common genetic pathways of FLD across two ethnic groups. This research offers a valuable framework for advancing personalized medicine and therapeutic strategies for FLD.

Exogenous hydrogen sulfide improves non-alcoholic fatty liver disease by inhibiting endoplasmic reticulum stress/NLRP3 inflammasome pathway.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (H2S) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous H2S in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous H2S on NAFLD. The results showed that NaHS (a donor of H2S) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous H2S ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous H2S suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous H2S inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of H2S for treating NAFLD.

Effects of dietary chlorogenic acid supplementation on laying performance, egg quality, antioxidant capacity, and liver lipid metabolism in late-peak laying hens

Effects of dietary chlorogenic acid supplementation on laying performance, egg quality, antioxidant capacity, and liver lipid metabolism in late-peak laying hens

MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS

BackgroundMyelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective.MethodsMSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function.ResultsOur findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A.ConclusionsWe suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS.

Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism.

The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance.

PLIN2 Promotes Lipid Accumulation in Ascites-Associated Macrophages and Ovarian Cancer Progression by HIF1α/SPP1 Signaling.

A major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites-mediated abdominal metastasis obscure. Here, a single-cell transcriptomic landscape of CD45+ immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high-grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2hi) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as "ascites-associated macrophages (AAMs)". AAMs are lipid-loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro-tumor functions. Finally, a PLIN2-targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer-promoting function and lipid-rich property of ascites-enriched PLIN2hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans-coelomic metastasis of OC.

Macrophages Unmasked: Their Pivotal Role in Driving Atherosclerosis in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that significantly increases the risk of cardiovascular diseases, particularly atherosclerosis (AS). Understanding the shared pathogenic mechanisms underlying SLE and AS is crucial for developing effective therapeutic strategies. Macrophages, as pivotal immune cells, play a critical role in the initiation and progression of atherosclerotic plaques within the context of SLE. This review delves into the molecular and cellular mechanisms governing macrophage activation and differentiation in response to SLE-related inflammatory mediators, highlighting their roles in lipid metabolism, plaque stability, and immune regulation. Additionally, we discussed the current treatment modalities for SLE and their impact on macrophage functionality, exploring these effects for atherosclerotic progression. By elucidating the intricate relationship between macrophages, SLE pathophysiology, and AS progression, this review underscores the need for a multidisciplinary approach in managing SLE and its cardiovascular complications, aiming to improve patient survival and quality of life through tailored therapeutic interventions addressing both autoimmune and cardiovascular pathologies.

Plasma levels of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) in chronic heart failure - predictors and prognostic relevance.

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is a transmembrane protein expressed on myeloid cells, including macrophages and microglia, and is involved in modulating inflammation and lipid metabolism. Elevated plasma levels of soluble TREM2 (sTREM2) have been associated with heart failure (HF) and neurodegenerative diseases such as Alzheimer's disease (AD). This post-hoc analysis explored the association of plasma sTREM2 with cognition and mortality in the Cognition.Matters-HF cohort of 148 chronic HF patients. Plasma sTREM2 levels were measured using a bead-based immunoassay, and the cohort was split into high and low sTREM2 groups based on a median concentration of 16.6 ng/ml. Higher sTREM2 levels were associated with worse cognitive performance, particularly in working memory (T = -2.67, p = 0.009) and visual/verbal memory (T = -2.16, p = 0.032), but not with cardiac function. In univariate cox regression, a higher plasma sTREM2 concentration was linked to increased mortality (HR = 1.28, 95% CI 1.05-1.57, p = 0.015), although this association did not remain significant after adjusting for age and heart failure severity (adjusted HR = 0.95, 95% CI 0.70-1.28, p = 0.720). These findings suggest that plasma sTREM2 reflects cognitive impairment more than cardiac dysfunction in HF, highlighting its potential as a biomarker for neuroinflammation in HF patients.

The role of lipids in promoting hair growth through HIF-1 signaling pathway

Understanding the underlying mechanisms regulating hair regeneration is crucial, especially given the increasing demand for effective drugs to treat hair loss, which remain not fully elucidated. In the present study, we found that lipid metabolism was attenuated in the scalp tissues of patients with androgenetic alopecia. Lipid supplementation in the culture medium upregulated hair growth-related genes and promoted the proliferation of human dermal papilla cells (DPCs). By using RNA-sequencing analysis and HIF-1α knockdown in DPCs, we found that HIF-1α is a potential candidate that governs lipid-reinforced upregulation of trichogenic genes. Finally, we assessed the hair growth-promoting effects of lipids using in vitro hair follicle organoids and found that lipids accelerated the elongation of hair-shaft-like structures. Our results highlight the importance of lipids in promoting hair growth through HIF-1 signaling, suggesting that this may be a promising target for the treatment of hair loss.

Gram-positive pathogens, inflammation, and the host lipid environment.

The host lipid environment is a barrier to bacterial infection that comprises antimicrobial fatty acids and impermeable lipids that keep infectious agents from penetrating tissues. Bacterial and host lipids also signal to the immune system to regulate inflammation. Notably, bacterial lipids activate Toll-like receptors to initiate cytokine production, immune cell recruitment, and oxidative burst to control infection. Bacterial pathogens must adapt to the lipid environment, including bactericidal host fatty acids and inflammatory lipids, in ways that promote persistence in diverse tissues. Here, we discuss current advances in the understanding of Staphylococcus aureus lipid interactions that contribute to inflammation and innate immunity and consider the complex roles of host inflammatory lipids in driving immune defenses and antibacterial activity. In addition, we endeavor to introduce similar processes in other Gram-positive pathogens. These recent studies highlight the growing body of knowledge on the effects of lipid metabolism on host immunity and pathogenesis.

Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model.

Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer's disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated CD11c+ microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1+ brain macrophages using an inducible APP-KI/Fit2iΔMφ transgenic mouse model. We demonstrated that reducing LD content in microglia and CX3CR1+ BAMs remarkably improved their phagocytic ability. Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma. Therefore, mitigating LD accumulation in brain macrophages provides perspectives for AD treatment.

Alternative lipid synthesis in response to phosphate limitation promotes antibiotic tolerance in Gram-negative ESKAPE pathogens.

The Gram-negative outer membrane protects bacterial cells from environmental toxins such as antibiotics. The outer membrane lipid bilayer is asymmetric; while glycerophospholipids compose the periplasmic facing leaflet, the surface layer is enriched with phosphate-containing lipopolysaccharides. The anionic phosphates that decorate the cell surface promote electrostatic interactions with cationic antimicrobial peptides such as colistin, allowing them to penetrate the bilayer, form pores, and lyse the cell. Colistin is prescribed as a last-line therapy to treat multidrug-resistant Gram-negative infections. Acinetobacter baumannii is an ESKAPE pathogen that rapidly develops resistance to antibiotics and persists for extended periods in the host or on abiotic surfaces. Survival in environmental stress such as phosphate scarcity, represents a clinically significant challenge for nosocomial pathogens. In the face of phosphate starvation, certain bacteria encode adaptive strategies, including the substitution of glycerophospholipids with phosphorus-free lipids. In bacteria, phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin are conserved glycerophospholipids that can form lipid bilayers, particularly in the presence of other lipids. Here, we demonstrate that in response to phosphate limitation, conserved regulatory mechanisms induce alternative lipid production in A. baumannii. Specifically, phosphate limitation induces formation of three lipids, including amine-containing ornithine and lysine aminolipids. Mutations that inactivate aminolipid biosynthesis exhibit fitness defects relative to wild type in colistin growth and killing assays. Furthermore, we show that other Gram-negative ESKAPE pathogens accumulate aminolipids under phosphate limiting growth conditions, suggesting aminolipid biosynthesis may represent a broad strategy to overcome cationic antimicrobial peptide-mediated killing.

Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells

Background: Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. Objectives: This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. Methods: We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. Results: Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. Conclusions: The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation.

Orlistat ameliorates lipid dysmetabolism in high-fat diet-induced mice via gut microbiota modulation

Orlistat reduces obesity by inhibiting gastrointestinal lipases, thereby blocking the absorption and accumulation of triglycerides in the intestine. It has been shown to improve lipid metabolism and alter intestinal microbial communities in animals and humans. However, the impact of Orlistat-induced changes in gut microbiota on obesity requires further investigation. In this study, we found that Orlistat significantly improved metabolic disorders, inhibited fat accumulation, and reshaped the structure of intestinal microbiota. Specifically, it reduced α diversity and increased the relative abundance of Verrucomicrobia and Akkermansia. Notably, antibiotic-induced gut microbiota depletion significantly weakened Orlistat’s effect on improving metabolic disorders. Furthermore, microbiota transplanted from Orlistat-treated mice effectively alleviated lipid metabolic disorders caused by a high-fat diet. We also observed that Orlistat increased food intake in mice and inhibited the synthesis of appetite-regulating hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg). However, antibiotic-depleted microbiota mitigated this inhibitory effect. Interestingly, although Orlistat altered the gut microbiota of mice, transplanting these microbiota did not inhibit the synthesis of appetite-regulating hormones. In summary, our results suggest that Orlistat can reshape the gut microbiota, and the altered gut microbiota works synergistically with Orlistat to improve metabolic disorders. This improvement is related to the increased abundance of Verrucomicrobia and Akkermansia.

Lipid metabolism and therapy: another year of exciting advances.

Lipid metabolism and therapy: another year of exciting advances.

Anticancer Chemotherapy-Induced Atherosclerotic Cardiovascular Disease: A Comprehensive Review

The introduction of anticancer agents has transformed oncology, significantly improving survival rates. However, these therapies have introduced unintended cardiovascular risks, with atherosclerovascular disease (ASCVD) emerging as a leading cause of morbidity and mortality among cancer survivors. The development of ASCVD in this population involves multifactorial mechanisms, including endothelial dysfunction, oxidative stress, systemic inflammation, and disrupted lipid metabolism. This review examines the various mechanisms through which anticancer chemotherapy contributes to ASCVD and highlights strategies for risk assessment and management. Each class of anticancer agents presents distinct cardiovascular challenges: anthracyclines induce oxidative stress and endothelial damage, promoting foam cell formation and plaque progression; taxanes and vascular endothelial growth factor (VEGF) inhibitors impair lipid metabolism and vascular stability; anti-metabolites exacerbate endothelial injury through reactive oxygen species; and mTOR inhibitors, hormonal therapies, tyrosine kinase inhibitors, and immune checkpoint inhibitors disrupt lipid profiles and inflammatory pathways, increasing the risk of plaque rupture and thrombosis. Mitigating chemotherapy-induced ASCVD necessitates a comprehensive, multidisciplinary approach. Detailed pre-treatment cardiovascular risk assessments must address traditional and cancer-specific risk factors, including demographics, pre-existing conditions, and modifiable behaviors such as smoking and inactivity. Pharmacological interventions like statins and angiotensin-converting enzyme (ACE) inhibitors, paired with lifestyle modifications, are essential to reducing ASCVD risk. In resource-limited settings, cost-effective strategies should be prioritized to enhance accessibility. Establishing cardio-oncology units facilitates care coordination, while long-term surveillance enables timely detection and intervention. These strategies collectively improve cardiovascular outcomes and survivorship in diverse patient populations.

Machine learning-based plasma metabolomics for improved cirrhosis risk stratification

BackgroundCirrhosis is a leading cause of mortality in patients with chronic liver disease (CLD). The rapid development of metabolomic technologies has enabled the capture of metabolic changes related to the progression of cirrhosis.MethodsThis study used proton nuclear magnetic resonance (1 H-NMR) serum metabolomics data from the UK Biobank (UKB) and employed elastic net-regularized Cox proportional hazards models to explore the role of metabolomics in cirrhosis risk stratification in patients with CLD. Metabolomic data were integrated with aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 score (FIB-4) to construct predictive models for cirrhosis risk. The model performance was assessed in both the derivation and validation cohorts.ResultsA total of 2,738 eligible patients were included in the analysis. Several metabolites showed an independent association with cirrhosis events (68 out of 168 metabolites after adjustment for age and sex, and 21 out of 168 metabolites after full adjustment). The integration of metabolomics with FIB-4 improved the predictive performance compared to FIB-4 alone (Harrell’s C: 0.717 vs. 0.696, ΔC = 0.021, 95% confidence interval [CI] 0.014–0.028, Net Reclassification Improvement [NRI]: 0.504 [0.488–0.520]). Similarly, the combination of metabolomics with APRI also improved predictive performance compared to APRI alone (Harrell’s C: 0.747 vs. 0.718, ΔC = 0.029, 95% CI 0.022–0.035, NRI: 0.378 [0.366–0.389]). Key metabolites, including branched-chain amino acids (BCAAs), lipids, and markers of oxidative stress, were identified as significant predictors. Pathway enrichment analysis revealed that disruptions in lipid and amino acid metabolism play a central role in the progression of cirrhosis.Conclusion1 H-NMR serum metabolomics significantly improves the prediction of cirrhosis risk in patients with CLD. The APRI + Metabolomics model demonstrated strong discriminatory power, with key metabolites involved in fatty acid and amino acid metabolism, providing a promising tool for the early screening of cirrhosis risk.