Modulation Of Lipid Metabolism Research Articles

Role of Rab35 in modulating lipid metabolism and viral entry during pseudorabies virus infection

Pseudorabies virus (PRV), the causative agent of Aujeszky's disease in swine, is a significant pathogen in veterinary medicine. Rab35 is a key regulatory GTPase involved in diverse cellular functions, including endocytic recycling, cytokinesis, and the regulation of the actin cytoskeleton. Although Rab35's roles in these processes are well-documented, its contribution to PRV replication dynamics had not been previously elucidated. Our study demonstrated that PRV infection led to an increase in Rab35 expression at both the mRNA and protein levels in both in vitro cell culture and in vivo models. Elevated Rab35 expression was associated with an acceleration of PRV replication, whereas knocking down Rab35 expression significantly impeded viral proliferation. Further investigation revealed that while Rab35 depletion did not impact the initial attachment of PRV to host cells, it critically suppressed subsequent viral entry and effectively obstructed the transcription of early PRV genes. The downregulation of Rab35 disrupted the expression of enzymes critical to lipid synthesis, which are upregulated during PRV infection. Moreover, Rab35 knockdown disrupted lipid dynamics necessary for the virus to integrate into clathrin-coated pits, a pivotal mechanism for PRV cellular entry. These findings collectively suggest that Rab35 plays a facilitatory role in PRV infection by modulating lipid metabolism and the viral entry process, thereby offering new insights into the complex intracellular mechanisms underlying PRV replication.

Mitochondrial apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways.

Mitochondria play central roles in metabolism and metabolic disorders such as type 2 diabetes. MIC26, a mitochondrial contact site and cristae organising system complex subunit, was linked to diabetes and modulation of lipid metabolism. Yet, the functional role of MIC26 in regulating metabolism under hyperglycemia is not understood. We used a multi-omics approach combined with functional assays using WT and MIC26 KO cells cultured in normoglycemia or hyperglycemia, mimicking altered nutrient availability. We show that MIC26 has an inhibitory role in glycolysis and cholesterol/lipid metabolism under normoglycemic conditions. Under hyperglycemia, this inhibitory role is reversed demonstrating that MIC26 is critical for metabolic adaptations. This is partially mediated by alterations of mitochondrial metabolite transporters. Furthermore, MIC26 deletion led to a major metabolic rewiring of glutamine use and oxidative phosphorylation. We propose that MIC26 acts as a metabolic "rheostat," that modulates mitochondrial metabolite exchange via regulating mitochondrial cristae, allowing cells to cope with nutrient overload.

Threonine modulates the STAT3-SCD1 pathway to reduce fatty acid metabolism in duck hepatocytes

Dietary threonine (Thr) is known to influence fat deposition in poultry, but the precise mechanisms behind its regulatory effects on hepatic lipid metabolism remain elusive. Prior research indicated that including supplemental Thr in the feed may influence STAT3 (Signal Transducer and Activator of Transcription 3) levels in the liver of meat ducks. Numerous studies have recorded the function of STAT3 in regulating fatty acid (FA) metabolism in mammals. The primary objective of this study was to investigate whether Thr influences FA metabolism and triglycerides (TG) deposition in duck liver by regulating STAT3 expression. Primary hepatocytes were isolated from duck embryos and treated for 36 h with different doses of Thr (0, 10, 25, 50, 200 μM) in vitro or with a constructed STAT3 overexpression plasmid to examine the content of FAs and TG. RNA-seq was used to detect changes in gene expression in hepatocytes following STAT3 overexpression. The results demonstrated that both the exogenous addition of Thr and the overexpression of STAT3 significantly suppressed the capacity of hepatocytes for FAs deposition (P < 0.05). The overexpression of STAT3 also inhibited TG accumulation under conditions in response to Thr deficiency (P < 0.01). Transcriptomic analyses indicated that the overexpression of STAT3 inhibits the activity of triglyceride metabolism and unsaturated fatty acid biosynthesis (P < 0.01). Finally, a dual-luciferase reporter test demonstrated that STAT3 may systematically target and inhibit SCD1 transcription (P < 0.01). The present study indicates that supplemental Thr (50 μM) inhibits hepatic FA deposition via the STAT3-SCD1 pathway. This work enhances our comprehension of the functional roles of Thr and STAT3 in modulating lipid metabolism within duck livers. Moreover, it provides a partial theoretical foundation for the nutritional prevention and pharmacological intervention of lipid metabolism disorders in poultry.

Roles of posttranslational modifications in lipid metabolism and cancer progression

AbstractLipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy.

Bacterial cellulose is a desirable biological macromolecule that can prevent obesity via modulating lipid metabolism and gut microbiota

Obesity has attracted great concern because of its undesirable effects on our life quality. Bacterial cellulose (BC) is a biological macromolecule that can improve gut homeostasis and lipid metabolism. However, its potential role in preventing obesity and associated mechanisms is still poorly understood. Herein, a supplement of BC was used to fully evaluate how it prevents obesity based on physio-biochemical and gut microbial analyses. Results showed that BC consumption helped decrease body and liver weight, and fat accumulation in kidney and epididymis. Correspondingly, glucose concentrations, total triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were reversed to the control levels. Consuming BC also improved liver fat metabolism and intestinal function, and alleviated ileum and epididymis inflammation. High-throughput sequencing suggested that a high-fat diet significantly decreased gut microbiota diversity, which could be reversed by consuming BC. A decreased Firmicutes and Proteobacteria and an increased Bacteroidetes following BC consumption were observed. The OTU-based analysis identified that Lachnospiraceae, Desulfovibrio, Lachnoclostridium, Blautia, Anaerotruncus, Bacteroides, Faecalibaculum, Bacteroidales S24–7 group, Prevotellaceae UCG-001 group, and Alloprevotella might be involved in obesity development or prevention. Our data suggest that BC is a good insoluble dietary fiber to prevent obesity via regulating lipid metabolism and gut microbiota.

Low-dose valine attenuates diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by enhancing leptin sensitivity and modulating the gut microbiome

Elevated circulating branched-chain amino acids (BCAAs) have been associated with obesity, insulin resistance, and MASLD, yet BCAA supplementation has been shown to provide protective outcomes towards the intervention of MASLD. Currently, there is a lack of study towards the contribution of the BCAA: valine on MASLD. This study investigates the effects of low-dose valine supplementation on MASLD in a high-fat/high-cholesterol diet (HFD) model. Low-dose valine was found to attenuate the progression of MASLD, significantly reducing body weight, liver weight, and eWAT weight, attenuating hyperglycemia and improving serum lipid profiles. It also decreased hyperleptinemia and enhanced hypothalamic leptin sensitivity, leading to reduced food intake. In the eWAT, metabolic flexibility was improved, as indicated by upregulated adipogenesis-related gene expressions and suppressed leptin expression. In the liver, valine improved hepatic leptin sensitivity, alleviated hepatic steatosis, and reduced triglycerides, cholesterol, TNFα, and IL-6 levels. Mechanistically, valine increased hepatic antioxidant capacity and modulated lipid metabolism and antioxidant pathways, downregulating de novo lipogenesis and cholesterol synthesis while increasing fatty acid oxidation, autophagy-related gene expressions. Moreover, hepatic AMPK pathway activity was enhanced, contributing to improved leptin sensitivity and signalling. Additionally, low-dose valine supplementation also modulated the gut microbiome, suggesting a multifaceted approach to managing MASLD.

A Comprehensive Review on the Anti-Obesity Potential of Limonia acidissima L., and its Bioactive Compounds: Mechanisms and Applications in Weight Management

Introduction: Obesity is a global health challenge associated with numerous metabolic disorders, including diabetes and cardiovascular disease. With growing interest in natural remedies for weight management, Limonia acidissima L., has garnered attention due to its rich bioactive composition. Objectives: This systematic review evaluates the anti-obesity potential of Limonia acidissima L., and its key bioactive compounds, including fibres, phytosterols, saponins, polyphenols, flavonoids, and ascorbic acid. Methods: A comprehensive search of databases such as PubMed, Scopus, and Google Scholar was conducted, focusing on studies published between 2000 and 2023 that investigated the metabolic effects of these compounds on lipid and carbohydrate metabolism, fat absorption, and glucose regulation. Results: The results demonstrated that Limonia acidissima L., significantly reduced body weight and fat mass, improved lipid profiles, and enhanced insulin sensitivity in both animal and human studies.Phytosterols and saponins played key roles in modulating lipid metabolism, while fibres and polyphenols were found to regulate carbohydrate metabolism and improve glycemic control. Additionally, the synergistic effects of multiple bioactive compounds amplified their collective anti-obesity potential, with few reported adverse effects, suggesting a favourable safety profile. The discussion highlights the multifaceted mechanisms through which Limonia acidissima L., combats obesity, emphasizing its ability to target multiple metabolic pathways simultaneously.While the findings are promising, the need for further large-scale clinical trials to validate these effects in diverse populations is underscored. Conclusions: In conclusion, Limonia acidissima L., emerges as a potent natural remedy for obesity management, with strong potential for inclusion in weight loss supplements and functional foods.Its bioactive compounds offer a comprehensive and safe approach to addressing the global obesity epidemic, although further research is needed to establish its long-term efficacy and optimal use.

In-vitro modulation of glucose and lipid metabolism by Lentinula edodes extracts in obesity and type 2 diabetes models

IntroductionLentinula edodes (shiitake mushroom) has been integral to Traditional Chinese Medicine (TCM) for centuries, with its cultivation dating back to the Song dynasty (960–1127) in China. Traditionally valued for its immune-boosting properties, L. edodes is now being studied for its potential in managing metabolic disorders like obesity and type 2 diabetes. This study examines the effects of L. edodes fruiting body extract on key metabolic pathways related to glucose metabolism and lipid regulation. MethodsFruiting body extracts of Lentinula edodes including water, ethanolic, methanolic, and hydroalcoholic (50:50, 75:25, 25:75) were tested on L6 myoblasts. The study evaluated glucose uptake, GLUT4 expression, p-AMPK activation, and gene expression levels of PPARγ, AMPK, UCP-1, and FASN. Comparisons were made with control groups and standards like berberine and insulin. ResultsThe hydroalcoholic extracts (50:50 and 75:25) significantly enhanced glucose uptake (p < 0.001) and GLUT4 translocation, similar to the effects of insulin (p < 0.0001) and berberine (p < 0.0001). These extracts also upregulated p-AMPK (p < 0.0001) and UCP-1 expression (7.621), indicating improved insulin sensitivity and thermogenic activity. Additionally, these extracts differentially regulated PPARγ and FASN, suggesting a complex interaction with lipid metabolism. Notably, FASN expression was highly upregulated in water extract (37.792), indicating potential implications for fatty acid synthesis and storage. DiscussionLentinula edodes shows significant potential as a functional food for managing obesity and diabetes, supporting traditional TCM practices with modern scientific evidence. The study suggests that L. edodes can modulate key metabolic pathways such as glucose uptake, AMPK signalling, PPARγ regulation, and upregulation of FASN and UCP-1, making it a promising natural therapeutic agent. Further research, including clinical trials, is necessary to confirm these benefits in humans and explore the underlying mechanisms.

Stimulation of neutral lipid synthesis via viral growth factor signaling and ATP citrate lyase during vaccinia virus infection.

Fatty acid metabolism can provide various products essential for viral infections. How vaccinia virus (VACV), the prototype of poxviruses, modulates fatty acid metabolism is not well understood. Here, we show that VACV infection results in increased neutral lipid droplet synthesis, the organelles that play a crucial role in storing and mobilizing fatty acids for energy production via β-oxidation. Citrate is the first tricarboxylic acid (TCA) cycle intermediate that can be transported to the cytosol to be converted to acetyl-CoA for de novo fatty acid biosynthesis. We found that VACV infection stimulates the S455 phosphorylation of ATP citrate lyase (ACLY), a pivotal enzyme that links citrate metabolism with lipid metabolism. We demonstrate that the inhibition of neutral lipid droplet synthesis and ACLY severely suppresses VACV replication. Remarkably, we found that virus growth factor (VGF)-induced signaling is essential for the VACV-mediated upregulation of ACLY phosphorylation and neutral lipid droplets. Finally, we report that VGF-induced EGFR-Akt pathway and ACLY phosphorylation are important for VACV stimulation of neutral lipid synthesis. These findings identified a new way of rewiring cell metabolism by a virus and a novel function for VGF in the governance of virus-host interactions through the induction of a key enzyme at the crossroads of the TCA cycle and fatty acid metabolism. Our study also provides a mechanism for the role played by VGF and its downstream signaling cascades in the modulation of lipid metabolism in VACV-infected cells.IMPORTANCENeutral lipid droplets are vital players in cellular metabolism. Here, we showed that VACV induces neutral lipid droplet synthesis in infected primary human foreskin fibroblasts and identified the cellular and viral factors needed. We identified VACV encoded growth factor (VGF) as an essential viral factor that induces cellular EGFR-Akt signaling to increase lipid droplets. Interestingly, VACV increases the S455 phosphorylation of ACLY, a key metabolic enzyme that sits at the crossroads of carbohydrate and lipid metabolism in a VGF-EGFR-Akt-dependent manner. We also found that ACLY is vital for VACV-induced lipid droplet synthesis. Our findings identified the modulation of ACLY by a virus and identified it as a potential target for antiviral development against pathogenic poxviruses. Our study also expands the role of growth factor signaling in boosting VACV replication by targeting fatty acid metabolism.

Adipose tissue/ heart lipid transport determines cardiac diastolic function

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and often occurring in obese individuals. Previous research has demonstrated that the modification of lipid metabolism can prevent the onset of diastolic dysfunction. In our project we have investigated how lipid transport influences the onset of diastolic dysfunction utilizing heart- and adipose tissue-specific knockdowns of the fatty acid (FA) transport protein 1 (FatP1) in Drosophila melanogaster. Methods We generated Drosophila with heart-specific (+/+; Hand4.2-GAL4/UAS-FatP1; tdtK/+) (cFatP1-KD) and adipose tissue-specific (+/+; ppl-GAL4/UAS-FatP1; tdtK/+) (atFat-P1-KD) FatP1 knockdowns using the UAS/GAL4 system. The flies' cardiomyocytes endogenously express tdTomato, facilitating fluorescence-based live imaging of the heart by high-resolution video fluorescence microscopy, as previously described. Cardiac morphology and cardiac lipid accumulation was monitored by confocal microscopy. Additionally, mitochondrial function was evaluated using the glycolytic Seahorse assay of whole hearts. Results Blocking FA-uptake into adipose tissue in atFatP1-KD flies resulted in a highly significant reduction in relaxation velocity (p=0.0009, WT vs. atFatP1-KD), indicative of diastolic dysfunction in flies, while contraction velocity and fractional shortening (systolic function) remained unchanged. Diastolic dysfunction was associated with a significant increase of cardiac lipid droplet (LD) quantity and size in flies lacking FatP1 in adipose tissue (p=0.0275 and p&amp;lt;0.0001, respectively, WT vs. atFatP1-KD). Cardiac mitochondrial function was significantly impaired in atFatP1-KD flies compared to WT flies. Reducing cardiac FA uptake in heart-specific FatP1 KD flies led to a decrease in end-diastolic diameter and a significant reduction in relaxation and contraction velocity (p&amp;lt;0.0001 and p=0.0001, respectively, WT vs. cFatP1-KD), suggesting impairment in both diastolic and systolic function. Interestingly, the number of cardiac LDs increased in cFATP1-KD, however their size decreased significantly resulting in an overall unchanged lipid content compared to WT flies (p=0.0475 and p=0.0367, respectively, WT vs. atFatP1-KD). Mitochondrial function showed no significant alterations. Conclusion This study demonstrates that reducing FA-uptake in adipose or cardiac tissue results in cardiac dysfunction in Drosophila melanogaster. Reduction of adipose tissue FA-uptake results exclusively in diastolic dysfunction likely mediated by cardiac lipid overload and subsequent mitochondrial dysfunction. In contrast, blockade of Fatp1-mediated cardiac FA-uptake induces diastolic/ systolic dysfunction which was unrelated to alterations in cardiac lipid content and mitochondrial dysfunction suggesting alternative mechanisms. These study identifies FatP1-mediated FA-uptake in adipose tissue as a potential therapeutic target for the treatment of diastolic dysfunction.

Impact of allogenic Fecal Microbiota Transplantation (FMT) on lipid parameters in patients with metabolic syndrome (MetS): a meta-analysis

Abstract Background Metabolic Syndrome (MetS) has long been considered a formidable global health concern, and impaired lipid metabolism has been one of its crucial clinical manifestations. Fecal Microbiota Transplantation (FMT) has emerged as a potential therapeutic strategy for MetS, nevertheless, prior meta-analyses have not only yielded conflicting outcomes, but as well predominantly centered on glycemic parameters, leaving the potential impact of FMT on lipid metabolism remained unexplored. Purpose This meta-analysis systematically assessed the influence of allogenic FMT on lipid parameters in MetS patients, unraveling its potential as an innovative therapeutic modality for MetS. Methods A meta-analysis was performed to explore the impact of allogenic FMT on lipid parameters (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TCHO] and triglycerides [TG]) in patients with MetS. Terms regarding FMT and metabolic syndrome were searched in PubMed/Medline, EMBASE, Web of Science, the Cochrane Library, and Scopus from the inception of the databases until 31 August 2023. Ten randomized controlled trials (RCTs) were included and mean difference (MD) of parameters were pooled using a fixed effects model. Subgroup analyses according to follow-up durations were performed, and this study was registered in PROSPERO. Results A total of 532 patients in 10 studies were included. Patients undergoing allogenic FMT manifested significantly higher HDL-c level compared with control group (receiving placebo or autologous FMT, pooled MD 0.06 [95% CI: 0.02, 0.10]), and the result remained consistent in the subgroup with 4 to 6 weeks of follow-up (MD 0.07 [95% CI: 0.02, 0.10]). Though overall pooled result did not manifest a significant LDL lowering effect (MD -0.08 [95% CI: -0.21, 0.05]), in subgroup analyses, a significantly lowered LDL level was observed at 12 weeks of follow-up (MD -0.34 [95% CI: -0.60, -0.08]). No significant difference was observed between allogenic FMT and control group concerning TCHO ant TG levels regardless of lengths of follow-up. Conclusions An overall higher level of HDL-C and lowered LDL-C at 12 weeks of follow-up was observed in MetS patients receiving allogenic FMT. The results indicated that gut microbiota from lean, healthy donors may display a beneficial effect on modulating lipid metabolism in patients with MetS. Allogenic FMT manifested promising therapeutic impact and could serve as a viable intervention for MetS patients. Future large-scale RCTs are required for further validation.

Human macrophages are immunnoprofiled by pericardial fluid small extracellular vesicles modulating lipid metabolism mechanisms

Abstract Background Coronary artery disease (CAD) is the main cause of myocardial infarction and consequent ischemic heart disease (IHD). Macrophages are central to CAD. Small extracellular vesicles (sEVs) can shuttle microRNAs and other molecular cargos from cell to cell, mediating response in target cells. Recent evidence supports the sEVs role in modulating macrophage phenotype. The pericardial fluid (PF) contains sEVs and immune cells including cavity-like macrophages. Purpose This study investigates whether PF-sEVs regulate macrophages, contributing to a specific immunophenotype in CAD patients. Methods PF was collected from CAD patients undergoing coronary bypass surgery (CABG) and non-atherosclerotic patients operated for mitral valve repair (control group). sEVs were isolated and characterised for size (Nanosight tracking analysi), tetrasapanin content (Nanoview chips) and microRNA content (RNA seq analysis). Monocytes from healthy donors were isolated from buffy coats and differentiated into macrophages following established protocols. Macrophages were incubated with either CAD-sEVs or non-CAD sEVs for 24h at 37oC. The cells were collected and processed for mRNA analyses (qRT-PCR) and flow cytometry. Further bioinformatics were employed to understand functional pathways targeted by PF-sEVs-miRNA. Results In line with the human-PF macrophages profile, exposure to CAD-sEVs reduces the anti-inflammatory profile of human macrophages. CAD-sEVs treated macrophages showed a CCR2-, CD36+low, CD206+low profile. While non-CAD-sEVs did not statistically differ from PBS nor untouched groups, CAD-sEVs increased the mRNA level of IL1a, IL1b, TNFa and decreased MRC1. Bioinformatic analysis showed that 861 miRNAs were decreased in the PF-sEVs from CAD patients compared to non-CAD. miRNA targets prediction and pathway analyses reported that clusters of PF-miRNAs could regulate CD36, decreased in PF-macrophages. Conclusions We demonstrate, that sEVs isolated from PF-CAD reduce the anti-inflammatory profile of human macrophages, and target crucial lipid metabolism pathways. These clinically relevant results could drive to decipher improved therapeutics to modulate the epicardial/myocardial immune response in CAD patients.

Dietary supplementation of probiotic Lactobacillus modulates metabolic dysfunction-associated steatotic liver disease and intestinal barrier integrity in obesity-induced mice.

The impact of Lacticaseibacillus paracasei NWAFU334 and Limosilactobacillus fermentum NWAFU0035 on the amelioration of liver function, oxidative stress reduction, and lipid metabolism modulation in mice subjected to an obesity-inducing high-fat diet (HFD) model was investigated. L. paracasei NWAFU334 and L. fermentum NWAFU0035 supplementations over 12weeks have been shown to have numerous beneficial effects in mice with induced obesity. These effects comprise the restoration of liver function and the reduction of oxidative stress within the liver. Furthermore, the supplementation led to a decreased content of fat accumulation in the liver, mitigation of the expression of inflammatory cytokines in the liver and colon, and a decrease in the expression levels of tight-junction proteins, for example, claudin-1, PPARγ, occludin, and ZO-1. Additionally, a notable improvement in the colonic expression proteins, including IL-6, TNF-α, IL-1β, Muc-2, Muc-3, Zo-1, claudin-1, and occludin. These proposed strains considerably decreased proinflammatory cytokines and influenced the regulation of lipid metabolism in the liver. These findings indicate that the potential mechanisms, primarily the impact of L. paracasei NWAFU334 and L. fermentum NWAFU0035 on obesity-induced liver function in mice, involve two regulated pathways: downregulation of lipogenesis and upregulation of gene expression related to fatty acid oxidation and lipolysis. In other words, these probiotic bacterial strains might be beneficial in reducing fat production and increasing fat breakdown in the liver. They may serve as effective therapeutic supplements for alleviating abnormalities induced by an HFD.

Apolipoprotein E Induces Lipid Accumulation Through Dgat2 That Is Prevented with Time-Restricted Feeding in Drosophila

Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer’s disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE’s role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism.

Regulation of Mitochondrial and Peroxisomal Metabolism in Female Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal-mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases.

The Impact of RNA Interference on Atherosclerotic Plaque Progression: A Meta-Analysis of Preclinical Studies

Background: Atherosclerosis, a chronic inflammatory disease characterized by the buildup of plaque within arteries, remains a leading cause of cardiovascular morbidity and mortality. RNA interference (RNAi) has emerged as a promising therapeutic strategy for atherosclerosis by targeting genes involved in plaque formation and progression. This meta-analysis aimed to evaluate the efficacy of RNAi in preclinical models of atherosclerosis. Methods: A systematic search of PubMed, Embase, and Web of Science databases was conducted from January 2013 to December 2023 to identify preclinical studies investigating the impact of RNAi on atherosclerotic plaque progression. Studies utilizing various RNAi modalities (siRNA, miRNA mimics/inhibitors, shRNA) targeting different genes involved in atherosclerosis were included. The primary outcome was plaque size reduction. Secondary outcomes included changes in plaque composition, lipid profiles, and inflammatory markers. A random-effects model was used to pool data and calculate standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic. Results: Seven preclinical studies met the inclusion criteria, encompassing a total of 210 animals. RNAi interventions significantly reduced atherosclerotic plaque size compared to controls (SMD -1.51; 95% CI -2.36 to -0.66; p&lt;0.00001; I²=12%). Analysis of secondary outcomes revealed favorable effects of RNAi on plaque composition, with a significant decrease in lipid content and an increase in collagen content. Furthermore, RNAi significantly improved lipid profiles by reducing total cholesterol and LDL-cholesterol levels. A significant reduction in inflammatory markers, such as TNF-α and IL-6, was also observed. Conclusion: This meta-analysis provides compelling evidence supporting the therapeutic potential of RNAi in attenuating atherosclerotic plaque progression in preclinical models. RNAi effectively reduced plaque size, improved plaque stability, and modulated lipid metabolism and inflammation.

The role of metabolic disorders in the development of atherosclerosis.

Atherosclerosis is a major risk factor for cardiovascular disease (CVD), which is the leading cause of death worldwide. Atherosclerosis is initiated by endothelial activation, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification) triggering vasoconstriction and activation of inflammatory pathways. This review focuses on the various stages in the development of atherosclerosis, ranging from endothelial dysfunction to plaque rupture. In addition, disorders of lipid, glucose and amino acid metabolism in atherosclerosis are considered here. The key pathological stages of metabolism disruption and their role in atherosclerosis are considered in detail which may be helpful for the more better understanding of atherosclerosis pathogenesis. Finally, some therapeutic approaches aimed at modulating lipid metabolism will also be presented which show the therapeutic targets (enzymes and transport proteins) which modulation can prevent further deterioration of patients symptoms.

D-Xylose Ameliorates Non-Alcoholic Fatty Liver Disease by Targeting Macrophage-expressed LYZ Gene.

This study investigates the therapeutic effects of D-Xylose, a natural sugar, on non-alcoholic fatty liver disease (NAFLD), focusing on the expression of the lysozyme gene (LYZ) in macrophages. Using the single-cell dataset GSE136103 for NAFLD, researchers analyzed macrophage populations and other groups utilizing the Seurat package in R, while a differential analysis was performed on the NAFLD dataset GSE61260 using the limma package. Both in vitro and in vivo models, including cell culture, mouse models, RT-qPCR, Western blot, ELISA, and histopathological analyses, were employed to examine the effect of D-Xylose on lipid accumulation, LYZ expression, blood lipid levels, and inflammatory responses. The study found a significant upregulation of LYZ in free fatty acid (FFA)-treated cells and mouse liver tissues, with a subsequent reduction after D-Xylose intervention. Treatment with D-Xylose and Amlodipine led to a notable decrease in lipid accumulation, as evidenced by reduced triglyceride and cholesterol levels. D-Xylose demonstrated a greater improvement in lipid metabolism than Amlodipine. Additionally, D-Xylose significantly mitigated inflammatory responses, reducing levels of inflammatory markers such as IL1R, IL6, MYS8, TNF, NF-κB, and IL-1. Furthermore, D-Xylose administration significantly reduced liver weight and liver index, with a positive impact on serum liver function and blood lipid levels. The findings suggest that D-Xylose could be a therapeutic intervention for NAFLD by targeting LYZ expression in macrophages, thereby modulating lipid metabolism and inflammatory responses.

Coffee Bioactive N-Methylpyridinium: Unveiling Its Antilipogenic Effects by Targeting De Novo Lipogenesis in Human Hepatocytes.

Type 2 diabetes and nonalcoholic fatty liver diseases (NAFLDs) are promoted by insulin resistance (IR), which alters lipid homeostasis in the liver. This study aims to investigate the effect of N-methylpyridinium (NMP), a bioactive alkaloid of coffee brew, on lipid metabolism in hepatocytes. The effect of NMP in modulating lipid metabolism is evaluated at physiological concentrations in a diabetes cell model represented by HepG2 cells cultured in a high-glucose medium. Hyperglycemia triggers lipid droplet accumulation in cells and enhances the lipogenic gene expression, which is transactivated by sterol regulatory element binding protein-1 (SREBP-1). Lipid droplet accumulation alters the redox status and endoplasmic reticulum (ER) stress, leading to the activation of the unfolded protein response and antioxidative pathways by X-Box Binding Protein 1(XBP-1)/eukaryotic Initiation Factor 2 alpha (eIF2α) Protein Kinase RNA-Like ER Kinase and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. NMP induces the phosphorylation of AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase α (ACACA), and improves the redox status and ER homeostasis, essential steps to reduce lipogenesis and lipid droplet accumulation. These results suggest that NMP may be beneficial for the management of T2D and NAFLD by ameliorating the cell oxidative and ER homeostasis and lipid metabolism.

Early pregnancy serum PFAS are associated with alterations in the maternal lipidome

Per- and polyfluoroalkyl substances (PFAS) have been detected in the blood of humans and animals worldwide. Exposure to some PFAS are associated with multiple adverse pregnancy outcomes. Existing literature has identified a strong association with PFAS exposure and metabolic dysfunction in humans, including modification of lipid metabolism. Using a subset of the Michigan Mother-Infant Pairs cohort (n=95), this study investigated associations between first trimester plasma levels of PFAS and maternal lipids and metabolites in the first trimester (T1), at the time of delivery (T3), and in the infant cord blood (CB) using untargeted shotgun lipidomics and metabolomics. Identifying PFAS-induced alterations in the maternal lipid- or metabolome at specific timepoints may help elucidate windows of susceptibility to adverse pregnancy outcomes. Out of 9 PFAS measured, 7 were detected in at least 20% of samples and were used for further analyses. PFOS and PFHxS were measured at the highest concentrations with medians of 5.76 ng/ml and 3.33 ng/ml, respectively. PFOA, PFNA, and PFDA had lower measured values with medians of < 1.2 ng/mL. PFHxS concentrations were positively associated with monounsaturated sphingomyelins (SMs) in T1 maternal plasma in adjusted models, determined by an adjusted p-value (q) < 0.1. PFHxS was positively associated with saturated and polyunsaturated SMs and inversely associated with saturated diacylglycerols in T1. Following metabolite-specific analysis, two mono-unsaturated diacylglycerols with carbon chain lengths of 32 and 35 were inversely associated with PFHxS in T1. In T3, only the association between PFHxS and SMs remained, but was attenuated. In addition, PFDA was associated with an increase in polyunsaturated plasmenyl-phosphatidylethanolamines in T3. No associations were identified between PFAS and infant cord blood lipids. Continued research into PFAS associated disruptions in lipid metabolism at sensitive stages of gestation may provide insight into the mechanisms that lead to adverse birth and pregnancy outcomes.