Regulation Of Lipid Metabolism Research Articles

A multi-target and responsive nanoplatform (MM/ZnS/ATV) combining H2S and atorvastatin for enhanced atherosclerosis therapy

Atherosclerosis, a chronic inflammatory disease characterized by the formation of atherosclerotic plaques in the arterial walls. The pathological process of atherosclerosis mainly contains lipid metabolism disorder, endothelial dysfunction, and progressive inflammation. Given the complexity of pathological process, treatments based on a single target might have very limited therapeutic efficacy. Thus, developing a nanoplatform to obtain an enhanced multi-target therapy is promising. Hydrogen sulfide (H2S) has various functions including anti-inflammation, anti-oxidation and endothelial protection. In this study, a responsive multi-target nanoplatform (MM/ZnS/ATV) combining the functions of H2S and atorvastatin was developed. The acidic microenvironment of the plaque can accelerate ZnS hydrolysis to trigger H2S and atorvastatin release. The responsive H2S release from ZnS can overcome the shortcomings of rapid H2S release from H2S donors in vivo. Furthermore, the ZnS hydrolysis-mediated H+ consumption in the microenvironment can reduce acidity to some extent. Results showed macrophage membranes (MM) coating reduced the phagocytosis of nanoparticles and increased the bioavailability. In vitro studies demonstrated that H2S release from MM/ZnS/ATV inhibited ROS-induced endothelial cell apoptosis and repaired the damaged endothelium. Moreover, atorvastatin released from MM/ZnS/ATV regulated lipid metabolism and reduced the blood lipid content. Both in vitro and in vivo studies confirmed MM/ZnS/ATV exhibited excellent therapeutic efficacy. Specifically, in vivo results showed that H2S combined with atorvastatin effectively reduced inflammatory infiltration, and promoted plaque regression and stabilization. Our study provides a promising strategy for atherosclerosis therapy.

The regulation of GSH/GPX4-mediated lipid accumulation confirms that schisandra polysaccharides should be valued equally as lignans

Ethnopharmacological relevanceAcetaminophen (APAP) induced liver injury (AILI) is a common cause of clinical hepatic damage and even acute liver failure. Our previous research has shown that Schisandra chinensis lignan extract (SLE) can exert a hepatoprotective effect by regulating lipid metabolism. Although polysaccharides from Schisandra chinensis (S. chinensis), like lignans, are important components of S. chinensis, their pharmacological activity and target effects on AILI have not yet been explored. Aim of the studyThis study aims to quantitatively reveal the role of SCP in the pharmacological activity of S. chinensis, and further explore the pharmacological components, potential action targets and mechanisms of S. chinensis in treating AILI. Materials and methodsThe therapeutic effect of SCP on AILI was systematically determined via comparing the efficacy of SCP and SLE on in vitro and in vivo models. Network pharmacology, molecular docking and multi-omics techniques were then used to screen and verify the action targets of S. chinensis against AILI. ResultsSCP intervention could significantly improve AILI, and the therapeutic effect was comparable to that of SLE. Notably, the combination of SCP and SLE did not produce mutual antagonistic effects. Subsequently, we found that both SCP and SLE could significantly reverse the down-regulation of GPX4 caused by the APAP modeling, and then further improving lipid metabolism abnormalities. ConclusionsHepatoprotective effects of SCP and SLE is most correlated with their regulation of GSH/GPX4-mediated lipid accumulation. This is the first exploration of the hepatoprotective effect and potential mechanism of SCP in treating AILI, which is crucial for fully utilizing S. chinensis and developing promising AILI therapeutic agents.

Lipid Droplet-Mitochondria Contacts in Health and Disease.

The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.

Exploring the action mechanism of Gegensan in the treatment of alcoholic liver disease based on network pharmacology and bioinformatics.

Gegensan (GGS) has been reported for the treatment of alcoholic liver disease (ALD), but its therapeutic mechanism is still unclear. This paper aims to determine the therapeutic mechanism and targets of action of GGS on alcoholic liver disease utilizing network pharmacology and bioinformatics. The active ingredients in GGS were screened in the literature and databases, and common targets of ALD were then obtained from public databases to construct the network diagram of traditional Chinese medicine-active ingredient targets. Based on the common targets, Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to find target enrichment pathways, and the core targets were screened out by combining differential analysis and protein-protein interaction network analysis. Molecular docking was performed to verify the binding effect between the core targets and the corresponding active ingredients. ALD and GGS have 84 common targets, corresponding to 91 active ingredients. After subsequent differential analysis and protein-protein interaction network analysis, 10 core targets were identified. Gene Ontology and KEGG enrichment analyses showed that the main BPs corresponding to the common targets included the response to lipopolysaccharide, inflammatory response, etc. The KEGG pathways involved in the regulation of the common targets included the lipid-atherosclerosis pathway and the alcoholic liver disease pathway, etc. Further molecular docking showed that the core targets CYP1A1, CYP1A2, CXCL8, ADH1C, MMP1, SERPINE1, COL1A1, APOB, MMP1, and their corresponding 4 active ingredients, Naringenin, Kaempferol, Quercetin, and Stigmasterol, have a greater docking potential. The above results suggest that GGS can regulate lipid metabolism and inflammatory response in the ALD process, and alleviate the lipid accumulation and oxidative stress caused by ethanol. This study analyzed the core targets and mechanisms of action of GGS on ALD, which provides certain theoretical support for the further development of GGS in the treatment of ALD, and provides a reference for the subsequent research on the treatment of ALD.

Dose-dependent effect of Dendrobium officinale polysaccharide on anti-aging in Caenorhabditis elegans: A metabolomics analysis focused on lipid and nucleotide metabolism regulation

Dendrobium officinale polysaccharide (DOP) has garnered attention for its potential anti-aging effects, yet the dose-dependent impact on aging, especially from a metabolomics perspective, remains less explored. Here, we investigated the dose-dependent effect of DOP on anti-aging in Caenorhabditis elegans, examining underlying mechanisms through metabolomics analysis. Based on food clearance assays, doses of 62.5, 125.0, and 250.0 mg/L of DOP were selected for lifespan experiments in C. elegans. Results indicated that both 125 and 250 mg/L DOP significantly extended lifespan, enhanced stress resistance, and preserved locomotion behavior, with superior effects observed at 250 mg/L. Metabolomics analysis revealed a dose-effect relationship between DOP concentration and 14 metabolites, primarily associated with lipid and nucleotide metabolism. Notably, metabolites including docosapentaenoic acid (DPA), arachidonic acid, uric acid, uridine 5′-diphosphogalactose (UDP-galactose), UDP-N-acetylglucosamine (UDP-GlcNAc), citric acid, l-Saccharopine, L-2-Aminoadipic acid, 5′-S-Methyl-5′-thioadenosine, 1-Linoleoyl glycerol, cyclic ADP-ribose, glycerol 3-phosphate (G3P), and adenosine exhibited increased levels with higher DOP doses, while palmitic acid levels declined with escalating DOP dose in the range from 62.5 to 250.0 mg/L. Furthermore, Pearson correlation analysis revealed strong associations between mean lifespan and levels of DPA, palmitic acid, G3P, UDP-galactose and UDP-GlcNAc. These findings underscore a significant relationship between lifespan extension and metabolic products of lipid and nucleotide metabolism in DOP-treated C. elegans, shedding light on potential mechanisms underlying anti-aging effects of DOP.

Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

Saikosaponin antidepressant mechanism: Improving the sphingolipid metabolism in the cortex via Apolipoprotein E and triggering neurovascular coupling

BackgroundSince the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works. PurposeIn this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms. MethodsAPOE-/- mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant. ResultsAPOE-/- mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE-/- mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice. ConclusionOur study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.

Cholesin receptor signalling is active in cardiovascular system-associated adipose tissue and correlates with SGLT2i treatment in patients with diabetes

BackgroundRecently deorphanized G protein-coupled receptor 146 (GPR146) was shown to respond to signal from a newly identified hormone—cholesin—and to play a role in hepatic lipid metabolism. However, the importance of its biological activity in human organism remains elusive, mainly due to the lack of studies on human tissues up to this point. This study aimed to identify the cholesin receptor-associated genes and clinical factors linked with their expression in cardiovascular system and associated adipose tissues.MethodsRight cardiac auricle, aortic wall, saphenous vein, and adipose tissue (periaortic-PAT, epicardial-EAT, thymic-TAT) samples were collected during coronary artery bypass grafting. Clinical records of the study participants were assessed for the presence of diabetes, medications taken and serum cholesterol levels. GPR146 mRNA expression in all gathered tissues was assessed with qPCR, and RNA seqencing was performed in selected tissues of 20 individuals to identify pathways associated with GPR146 expression.ResultsWe included 46 participants [37 male, 23 with type 2 diabetes, median age 68.50 (Q1–Q3: 63.00–72.00) years, BMI 28.39 (26.06–31.49) kg/m2]. GPR146 expression in adipose tissues significantly correlated with BMI, c-peptide, total cholesterol, and LDL concentrations. Selected metabolic pathways were significantly and positively enriched in GPR146-dependent manner. GPR146-coexpressed genes contained key regulators of lipid metabolism involved in such pathways as fatty acid metabolism, tricarboxilic acid cycle and peroxisomal metabolism. Those genes correlated positively with serum concentrations of LDL, HDL, and total cholesterol. SGLT2i treatment was associated with inversion of GPR146-related signature in EAT, suggesting potential impact on cholesin-GPR146 network.ConclusionsGPR146 expression is associated with serum lipids and metabolically-relevant transcriptomic changes in EAT similar to SGLT2i-associated ones.Graphical abstract

The mechanism of SSO regulating SiO(2)-induced lipid metabolism disorders in macrophages was explored based on lipid metabolomics

Objective: To investigate the mechanism of Sulfo-N-succinimidyloleate (SSO) regulating lipid metabolism disorder induced by silicon dioxide (SiO(2)) . Methods: In March 2023, Rat alveolar macrophages NR8383 were cultured in vitro and randomly divided into control group (C), SSO exposure group (SSO), SiO(2) exposure group (SiO(2)) and SiO(2)+SSO exposure group (SiO(2)+SSO). NR8383 cells were exposure separately or jointly by SSO and SiO(2) for 36 h to construct cell models. Immunofluorescence and BODIPY 493/ 503 staining were used to detect cluster of differentiation (CD36) and intracellular lipid levels, the protein expression levels of CD36, liver X receptors (LXR), P-mammalian target of rapamycin (P-mTOR) and cholinephosphotransferase 1 (CHPT1) were detected by Western blot, respectively, and lipid metabolomics was used to screen for different lipid metabolites and enrichment pathways. Single-factor ANOVA was used for multi-group comparison, and LSD test was used for pair-to-group comparison. Results: SiO(2) caused the expression of CD36 and P-mTOR to increase (P=0.012, 0.020), the expression of LXR to decrease (P=0.005), and the intracellular lipid level to increase. After SSO treatment, CD36 expression decreased (P=0.023) and LXR expression increased (P=0.000) in SiO(2)+SSO exposure group compared with SiO(2) exposure group. Metabolomics identified 87 different metabolites in the C group and SiO(2) exposure group, 19 different metabolites in the SiO(2) exposure group and SiO(2)+SSO group, and 5 overlaps of different metabolites in the two comparison groups, they are PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), and Sphinganine. In addition, the differential metabolites of the two comparison groups were mainly concentrated in the glycerophospholipid metabolism and sphingolipid metabolism pathways. The differential gene CHPT1 in glycerophospholipid metabolic pathway was verified, and the expression of CHPT1 decreased after SiO(2) exposure. Conclusion: SSO may improve SiO(2)-induced lipid metabolism disorders by regulating PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), SPA, glycerophospholipid metabolism and sphingolipid metabolism pathways.

Integrative analysis reveals the anti-obesity roles of Poria cocos polysaccharides through beneficial effects on gut microbiota

Obesity is a global health problem that is characterized with metabolic disorders. And new medicine for obesity is developed needfully. In this study, we investigated the beneficial anti-obesity effects of Poria Cocos polysaccharides (PCP) through modulation of fatty acid metabolism and gut microbiota in vivo. PCP, the functional nutrient components, have gained attention due to emerging pharmacological properties. Plant polysaccharides have also shown promising application for the treatment of metabolic diseases. However, the correlative mechanisms of PCP-exhibited anti-obesity effects via targeting fatty acid metabolism remain unclear. Therefore, we employed a network pharmacology approach combined with 16S ribosomal RNA (rRNA) sequencing to explore the anti-obesity actions, targets, and metabolic mechanisms exerted by PCP. By using public databases for comprehensive analysis, we identified 35 genes that were mutual with PCP, obesity, and fatty acid metabolism. These genes could play crucial roles in inflammation, adipogenesis, lipid metabolism, and insulin signaling regulation. Furthermore, current results demonstrated that PCP attenuated the activation of the inflammatory signaling pathway in adipose tissue caused by high-fat diet (HFD) in mice. PCP showed benefits in reducing the inflammatory processes and improving metabolic disturbance. Base on metagenomic sequencing report, PCP might restore the gut microbiota composition and diversity, thereby meliorating fatty acid metabolism and energy homeostasis. Further 16S rRNA findings revealed changes in gut microbial profiles, including altered Eisenbergiella, Dorea, Proteiniphilum and Lachnospira in response to PCP treatment. Overall, our study provides insights into the beneficial actions of PCP for exhibiting anti-obesity effects through improving fatty acid metabolism and gut microbiota homeostasis in vivo, suggesting that PCP may be a therapeutic strategy for obesity and metabolic disorders.

SPDYC serves as a prognostic biomarker related to lipid metabolism and the immune microenvironment in breast cancer.

Breast cancer remains the most common malignant carcinoma among women globally and is resistant to several therapeutic agents. There is a need for novel targets to improve the prognosis of patients with breast cancer. Bioinformatics analyses were conducted to explore potentially relevant prognostic genes in breast cancer using The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases. Gene subtypes were categorized by machine learning algorithms. The machine learning-related breast cancer (MLBC) score was evaluated through principal component analysis (PCA) of clinical patients' pathological statuses and subtypes. Immune cell infiltration was analyzed using the xCell and CIBERSORT algorithms. Kyoto Encyclopedia of Genes and Genomes enrichment analysis elucidated regulatory pathways related to speedy/RINGO cell cycle regulator family member C (SPDYC) in breast cancer. The biological functions and lipid metabolic status of breast cancer cell lines were validated via quantitative real-time polymerase chain reaction (RT‒qPCR) assays, western blotting, CCK-8 assays, PI‒Annexin V fluorescence staining, transwell assays, wound healing assays, and Oil Red O staining. Key differentially expressed genes (DEGs) in breast cancer from the TCGA and GEO databases were screened and utilized to establishthe MLBC score. Moreover, the MLBC score we established was negatively correlated with poor prognosis in breast cancer patients. Furthermore, the impacts of SPDYC on the tumor immune microenvironment and lipid metabolism in breast cancer were revealed and validated. SPDYC is closely related to activated dendritic cells and macrophages and is simultaneously correlated with the immune checkpoints CD47, cytotoxic T lymphocyte antigen-4 (CTLA-4), and poliovirus receptor (PVR). SPDYC strongly correlated with C-C motif chemokine ligand 7 (CCL7), a chemokine that influences breast cancer patient prognosis. A significant relationship was discovered between key genes involved in lipid metabolism and SPDYC, such as ELOVL fatty acid elongase 2 (ELOVL2), malic enzyme 1 (ME1), and squalene epoxidase (SQLE). Potent inhibitors targeting SPDYC in breast cancer were also discovered, including JNK inhibitor VIII, AICAR, and JW-7-52-1. Downregulation of SPDYC expression in vitro decreased proliferation, increased the apoptotic rate, decreased migration, and reduced lipid droplets. SPDYC possibly influences the tumor immune microenvironment and regulates lipid metabolism in breast cancer. Hence, this study identified SPDYC as a pivotal biomarker for developing therapeutic strategies for breast cancer.

Enhancing bioactive content in Malus sylvestris peel extract for antioxidant source using microwave-assisted extraction (MAE) and predicting the potential of ant nests

Background The apple peel is one of the byproducts of apple beverage production that is still underutilized. While considerable information regarding apple peel extract is available, its utilization remains limited. Yet, apple peel contains numerous bioactive components that offer various health benefits. Based on this, information regarding the bioactive components in apple peel and their health potential is required. Methods The research consisted of two stages, namely Stage 1, which involved in silico analysis of the bioactive content in apples and predicted the potential of ant nests using the Structural Activity Relationship (SAR) approach Pass Online. In Stage 2, in vitro analysis of apple peel extraction as a natural antioxidant source was conducted using treatment time radiation (3 minutes, 6 minutes, 9 minutes, and 12 minutes). The extract was characterized based on phenolic, flavonoid, antioxidant activity, quercetin, and functional groups using Fourier Transform Infrared Spectroscopy (FTIR). Results Stage 1: gave results that several bioactive were identified such as chlorogenic acid, epicatechin, phloridzin, catechin, hyperoside, quercitrin, quercetin, and pectin. Based on SAR, the bioactive compounds have functional potential as anti-inflammatory, lipid metabolism regulators, free radical scavengers, lipid peroxidase inhibitors, antihypercholesterolemic, and insulin promoters. Stage 2: Radiation times of the MAE method had a significant effect (P&lt;0.05) on the phenolic content, and antioxidant activity and was highly significant (P&lt;0.01) on the flavonoid content of Malus sylvestris. Radiation time for 12 minutes of MAE gave higher phenolic, flavonoid, and antioxidant activity of Malus sylvestris peel extract. The IR spectra of the Malus sylvestris extract increased as the radiation time increased. Conclusions The optimum radiation time was at 12 minutes with the result of phenolic content at 14.73 mg GAE/g, flavonoid content at 29,62 ppm, antioxidant activity at 95,09%, and the IR spectra at 1031.92 cm−1, 1390.68 cm−1, 2833.43 cm−1, 2945.3 cm−1, 3346.5 cm−1, 3354.21 cm−1.

Codonopsis pilosula polysaccharides (CPP) intervention alleviates sterigmatocystin (STC)-induced liver injury and gut microbiota dysbiosis

Codonopsis pilosula polysaccharides (CPP), the main active ingredient of Codonopsis pilosula, has gained significant attention as a liver-protective agent. Previous studies have demonstrated that CPP could alleviate gut microbiota dysbiosis in colitis or obese mice. However, the effects of CPP on mycotoxin-induced liver injury and gut microbiota dysbiosis are still poorly understood. In this study, we aimed to investigate the protective effects of CPP on sterigmatocystin (STC)-induced liver injury, as well as its regulatory effects on gut microbiota. Our results revealed that CPP intervention significantly alleviated STC-induced liver injury, as evidenced by decreased liver index, reduced liver histopathological changes, and modulation of related molecular markers. Additionally, we found that CPP could alleviate liver injury by reducing liver inflammation and oxidative stress, inhibiting hepatocyte apoptosis, and regulating lipid metabolism. Notably, we also observed that CPP could alleviate STC-induced gut microbiota dysbiosis by modulating the diversity and richness of gut microbiota, suggesting that gut microbiota modulation may also serve as a mechanism for CPP-mediated remission of liver injury. In summary, our study not only provided a new theoretical basis for understanding the hepatotoxicity of STC and the protective effects of CPP against STC-induced liver injury, but also provided new perspectives for the application of CPP in the fields of food, healthcare products, and medicine.

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show region-and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.

Day and Night Reversed Feeding Aggravates High-Fat Diet-Induced Abnormalities in Intestinal Flora and Lipid Metabolism in Adipose Tissue of Mice

BackgroundThe incongruity between dietary patterns and the circadian clock poses an elevated risk for metabolic health issues, particularly obesity and associated metabolic disorders. The intestinal microflora engages in regulating various physiological functions of the host through its metabolites. ObjectivesThis study aimed to investigate the impact of reversed feeding schedules during the day and night on intestinal flora and lipid metabolism in high-fat diet-induced obese mice. MethodsMice aged 8–10 wk were subjected to either daytime or nighttime feeding and were administered a control or high-fat diet for 18 wk. At the end of the experiment, various assessments were conducted, including analysis of serum biochemic indices, histologic examination, evaluation of gene and protein expression in adipose tissue, and scrutiny of changes in intestinal microbial composition. ResultsThe results showed that day-night reversed feeding caused an increase in fasting blood glucose and exacerbated the high-fat diet-induced weight gain and lipid abnormalities. The mRNA expression levels of Leptin and Dgat1 were increased by day-night reversed feeding, which also reduced the expression level of adiponectin under the high-fat diet. Additionally, there was a significant increase in the protein concentrations of PPARγ, SREBP1c, and CD36. Inverted feeding schedules led to a reduction in intestinal microbial diversity, an increase in the abundance of inflammation-related bacteria, such as Coriobacteriaceae_UCG-002, and a suppression of beneficial bacteria, including Akkermansia, Candidatus_Saccharimonas, Anaeroplasma, Bifidobacterium, Carnobacterium, and Odoribacter. Acinetobacter exhibited a significant negative correlation with Leptin and Fasn, suggesting potential involvement in the regulation of lipid metabolism. ConclusionsThe results elucidated the abnormalities of lipid metabolism and intestinal flora caused by day-night reversed feeding, which exacerbates the adverse effects of a high-fat diet on lipid metabolism and intestinal microflora. This reversal in feeding patterns may disrupt both intestinal and lipid metabolism homeostasis by altering the composition and abundance of intestinal microflora in mice.

Effects of gut microbiota-derived short-chain fatty acids on cognitive impairment: An in-silico study

Increasing evidence suggests that gut microbiota-derived metabolites affect cognitive function, but the underlying molecular mechanisms remain unclear. In this study, mechanisms of cognitive dysfunction that can be targeted by acetic acid and butyric acid were analyzed using literature review, Metascape, Mienturnent, Passonline, and WissADME. We found that acetic acid and butyric acid may regulate important genes (PPARG, CASP3, IL1B, SOD2, and TNF) that protect against cognitive decline. We also found microRNAs (hsa-miR-17-5p and hsa-miR-20a-5p) and transcription factors (RELA and NFKB1) that play a critical role in this protective mechanism. The AGE-RAGE signaling pathway and apoptosis pathways also emerged as crucial to understanding the underlying pathophysiological mechanisms. Our findings are further supported by the physicochemical properties and pharmacokinetic profiles of acetic acid and butyric acid, which demonstrate remarkable intestinal absorption, ability to penetrate the blood-brain barrier, and non-inhibition of CYP450 enzymes. Our study provides further evidence of the therapeutic potential of butyric acid in managing cognitive impairment, including its anti-inflammatory properties, stimulation of insulin synthesis, and regulation of lipid metabolism. We also identified several promising treatments for cognitive impairment, including miRNA sponges, mesalazine, omega-3 fatty acids, pomalidomide, and andrographolide. Focused investigations into the apoptosis and AGE-RAGE signaling pathways, miRNA sponges, promising drugs, and the role of gut microbiota in cognitive function are warranted.

Supplementation of Mangiferin to a High-Starch Diet Alleviates Hepatic Injury and Lipid Accumulation Potentially through Modulating Cholesterol Metabolism in Channel Catfish (Ictalurus punctatus).

Starch is a common source of carbohydrates in aqua feed. High-starch diet can cause hepatic injury and lipid accumulation in fish. Mangiferin (MGF) can regulate lipid metabolism and protect the liver, but there is limited research on its effects in fish. In the present study, we investigated whether MGF could ameliorate high-starch-induced hepatic damage and lipid accumulation in channel catfish. The channel catfish (Ictalurus punctatus) were fed one of four experimental diets for eight weeks: a control diet (NCD), a high-starch diet (HCD), an HCD supplemented with 100 mg/kg MGF (100 MGF), and an HCD supplemented with 500 mg/kg MGF (500 MGF). The results demonstrated that the weight gain rate (WGR) (p = 0.031), specific growth rate (SGR) (p = 0.039), and feed conversion efficiency (FCE) (p = 0.040) of the 500 MGF group were significantly higher than those of the NCD group. MGF supplementation alleviated liver damage and improved antioxidant capacity (T-AOC) compared to those of the HCD group (p = 0.000). In addition, dietary MGF significantly reduced plasma glucose (GLU) (p = 0.000), triglyceride (TG) (p= 0.001), and low-density lipoprotein cholesterol (LDL) (p = 0.000) levels. It is noteworthy that MGF significantly reduced the plasma total cholesterol (TC) levels (p = 0.000) and liver TC levels (p = 0.005) of channel catfish. Dietary MGF improves cholesterol homeostasis by decreasing the expression of genes that are involved in cholesterol synthesis and transport (hmgcr, sqle, srebf2, sp1, and ldlr) and increasing the expression of genes that are involved in cholesterol catabolism (cyp7a1). Among them, the largest fold decrease in squalene epoxidase (sqle) expression levels was observed in the 100 MGF or 500 MGF groups compared with the HCD group, with a significant decrease of 3.64-fold or 2.20-fold (p = 0.008). And the 100 MGF or 500 MGF group had significantly decreased (by 1.67-fold or 1.94-fold) Sqle protein levels compared to those of the HCD group (p = 0.000). In primary channel catfish hepatocytes, MGF significantly down-regulated the expression of sqle (p = 0.030) and reduced cholesterol levels (p = 0.000). In NCTC 1469 cells, MGF significantly down-regulated the expression of sqle (p = 0.000) and reduced cholesterol levels (p = 0.024). In conclusion, MGF effectively inhibits sqle expression and reduces cholesterol accumulation. The current study shows how MGF supplementation regulates the metabolism and accumulation of cholesterol in channel catfish, providing a theoretical basis for the use of MGF as a dietary supplement in aquaculture.

Bile acid profiles and messenger RNA expression of bile acid-related genes in the liver of dairy cows with high versus normal body condition

Bile acids (BA) play a crucial role not only in lipid digestion but also in the regulation of overall energy homeostasis, including glucose and lipid metabolism. The aim of this study was to investigate BA profiles and mRNA expression of BA-related genes in the liver of high versus normal body condition in dairy cows. We hypothesized that body condition and the transition from gestation to lactation affect hepatic BA concentrations as well as the mRNA abundance of BA-related receptors, regulatory enzymes, and transporters. Therefore, we analyzed BA in the liver as well as the mRNA abundance of BA-related synthesizing enzymes, transporters, and receptors in the liver during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into groups with high body condition score (BCS) (HBCS; n = 19) or normal BCS (NBCS; n = 19) based on BCS and backfat thickness (BFT). Cows were fed diets aimed at achieving the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until they were dried off at wk 7 before parturition. Both groups were fed identical diets during the dry period and subsequent lactation. Liver biopsies were taken at wk -7, 1, 3, and 12 relative to parturition. For BA measurement, a targeted metabolomics approach with LC-ESI-MS/MS was used to analyze BA in the liver. The mRNA abundance of targeted genes related to BA-synthesizing enzymes, transporters, and receptors in the liver was analyzed using microfluidic quantitative PCR. In total, we could detect 14 BA in the liver: 6 primary and 8 secondary BA, with glycocholic acid (GCA) being the most abundant one. The increase of glycine-conjugated BA after parturition, in parallel to increasing serum glycine concentrations may originate from an enhanced mobilization of muscle protein to meet the high nutritional requirements in early lactating cows. Higher DMI in NBCS cows compared with HBCS cows was associated with higher liver BA concentrations such as GCA, deoxycholic acid (DCA), and cholic acid (CA). The mRNA abundance of BA-related enzymes measured herein suggests the dominance of the alternative signaling pathway in the liver of HBCS cows. Overall, BA profiles and BA metabolism in the liver depend on both, the body condition and lactation-induced effects in periparturient dairy cows.

FUS3: Orchestrating soybean plant development and boosting stress tolerance through metabolic pathway regulation

Soybean research has gained immense attention due to its extensive use in food, feedstock, and various industrial applications, such as the production of lubricants and engine oils. In oil crops, the process of seed development and storage substances accumulation is intricate and regulated by multiple transcription factors (TFs). In this study, FUSCA3 (GmFUS3) was characterized for its roles in plant development, lipid metabolism, and stress regulation. Expressing GmFUS3 in atfus3 plants restored normal characteristics observed in wild-type plants, including cotyledon morphology, seed shape, leaf structure, and flower development. Additionally, its expression led to a significant increase of 25% triacylglycerols (TAG) and 33% in protein levels. Transcriptomic analysis further supported the involvement of GmFUS3 in various phases of plant development, lipid biosynthesis, lipid trafficking, and flavonoid biosynthesis. To assess the impact of stress on GmFUS3 expression, soybean plants were subjected to different stress conditions, and the its expression was assessed. Transcriptomic data revealed significant alterations in the expression levels of approximately 80 genes linked to reactive oxygen species (ROS) signaling and 40 genes associated with both abiotic and biotic stresses. Additionally, GmFUS3 was found to regulate abscisic acid synthesis and interact with nucleoside diphosphate kinase 1, which is responsible for plant cellular processes, development, and stress response. Overall, this research sheds light on the multifaceted functions of GmFUS3 and its potential applications in enhancing crop productivity and stress tolerance.

Allergic inflammation triggers dyslipidemia via IgG signalling.

Allergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. We used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TGs) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction. We found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TGs and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TGs in 59 patients after undergoing an allergic reaction. Overall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.