Regulation Of Lipid Metabolism Research Articles

Efficacy of DHA-enriched phosphatidylserine and its underlying mechanism in alleviating polystyrene nanoplastics-induced hepatotoxicity in mice

ObjectivePlastic pollution has become a global pollution problem that cannot be ignored. As the main destination of human oral intake, the toxic effects of plastic on the digestive system represented by the intestine and liver are the focus of current research. Marine-derived DHA-PS has a variety of biological activities, mainly focusing on improving brain function and regulating lipid metabolism. However, whether it has an improvement effect on PS-NPs-induced hepato-intestinal injury and the underlying mechanism remain unclear. MethodsA murine liver injury model was established by gavage of PS-NPs for six weeks. By integrating approaches from lipidomics, transcriptomics, and gut microbiota analysis, the molecular mechanism by which DHA-PS alleviates PS-NPs-induced murine hepatotoxicity was explored through the “gut-liver axis”. ResultsOur findings reveal that prolonged exposure to PS-NPs results in significant murine liver damage and dysfunction, characterized by increased oxidative stress and inflammation, along with exacerbated hepatic lipid accumulation. Mechanistically, PS-NPs disrupt the hepatic SIRT1-AMPK pathway by suppressing the expression of SIRT1, AMPKα, and PPARα, while enhancing the expression of SREBP-1c, ultimately leading to disordered hepatic lipid metabolism. The sphingolipid and glycerophospholipid metabolic pathways were particularly affected. Additionally, in agreement with transcriptomic analyses, PS-NPs activate the hepatic TLR4/NF-κB pathway. At the same time, exposure to PS-NPs decreases the expression of ZO-1, occludin, and claudin-1, diminishes the relative abundance of beneficial gut bacteria (norank_f_Muribaculaceae, Akkermansia, and norank_f_norank_o_Clostridia_UCG-014), and increases the prevalence of pathogenic gut bacteria (Coriobacteriaceae_UCG-002 and Desulfovibrio), exacerbating liver injury through the gut-liver axis. However, administering DHA-PS (50 mg/kg) effectively alleviated these injuries. ConclusionThis study was the first to employ multi-omics techniques to elucidate the potential mechanisms underlying hepatotoxicity induced by PS-NPs, thereby supporting the use of DHA-PS as a dietary supplement to mitigate the effects of nanoplastic pollutants.

Regulation of Age-Related Lipid Metabolism in Ovarian Cancer.

Aging microenvironment of OC may be regulated by S100a8 and S100a9 secreted by adipocytes, preadipocytes, or neutrophils through affecting the lipid metabolism, such as FFA (18:3).

ANGPTL4-the Link Binding Lipid Metabolism and Inflammation.

Angiopoietin-like 4 (ANGPTL4) belongs to the family of angiopoietin- like proteins. The involvement of ANGPTL4 in various aspects of lipid metabolism and inflammation has become an important area of research. A thorough search on PubMed related to ANGPTL4, lipid metabolism, and inflammation was performed. Over the past two decades, the recognition of ANGPTL4 as a potent regulator of lipid metabolism has substantially increased. As part of the senescence-associated secretory phenotype, ANGPTL4 also serves as an inflammatory mediator. Considering the advancements in ANGPTL4 research, we have highlighted that ANGPTL4 acts as a key node linking lipid metabolism and inflammation. ANGPTL4 impacts inflammation by regulating lipid metabolism. It affects critical enzymes (lipoprotein lipase, hepatic lipase, endothelial lipase, and acetyl-CoA carboxylase), regulatory factors (AMPK, cAMP, SLC7A11, GPX4, and mTOR), and receptors (LepR, CD36, and PPARγ) of lipid oxidation, synthesis, and peroxidation, thereby affecting immune cells and inflammatory pathways. Understanding the potential association and the therapeutic value of ANGPTL4 for regulating lipid metabolism and inflammation could contribute to drug discovery and therapeutic development.

Application of galactosylated albumin for targeted delivery of triptolide to suppress hepatocellular carcinoma progression through inhibiting de novo lipogenesis

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-associated death globally with a lack of efficient therapy. The pathogenesis of HCC is a complex and multistep process, highly reliant on de novo lipogenesis, from which tumor cells can incorporate fatty acids to satisfy the necessary energy demands of rapid proliferation and provide survival advantages. Triptolide (TP) is a bioactive ingredient exhibiting potent abilities of anti-proliferation and lipid metabolism regulation, but its clinical application is constrained because of its toxicity and non-specific distribution. The present study has developed galactosylated bovine serum albumin nanoparticles loaded with TP (Gal-BSA-TP NPs) to alleviate systemic toxicity and increase tumor-targeting and antitumor efficacy. Furthermore, Gal-BSA-TP NPs could inhibit de novo lipogenesis via the p53-SREBP1C-FASN pathway to deprive the fuel supply of HCC, offering a specific strategy for HCC treatment. In general, this study provided a biocompatible delivery platform for targeted therapy for HCC from the perspective of de novo lipogenesis.

Spatial regulation of NMN supplementation on brain lipid metabolism upon subacute and sub-chronic PM exposure in C57BL/6 mice

BackgroundAtmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed.ResultsIn this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis.ConclusionsThis study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.

Hepatoprotective effects of magnolol in fatty liver hemorrhagic syndrome hens through shaping gut microbiota and tryptophan metabolic profile

BackgroundMagnolol (MAG) exhibits hepatoprotective activity, however, whether and how MAG regulates the gut microbiota to alleviate fatty liver hemorrhagic syndrome (FLHS) remains unclear. Therefore, we investigated the mechanism of MAG in FLHS laying hens with an emphasis on alterations in the gut–liver axis. We randomly divided 540 56-week-old Hy-line white laying hens with FLSH into 4 groups. The birds were fed a high-fat low-protein (HFLP) diet (CON) or HELP diets supplemented with 200, 400, and 600 mg/kg of MAG (M1, M2, and M3, respectively) for 9 weeks.ResultsMagnolol supplementation increased the laying rate and ameliorated hepatic damage and dysfunction by regulating lipid metabolism, improving intestinal barrier function, and shaping the gut microbiota and tryptophan metabolic profiles. Dietary MAG supplementation downregulated the expression of lipid synthesis genes and upregulated the expression of lipid transport genes at varying degrees. The intestinal barrier function was improved by 200 and 400 mg/kg of MAG supplementation, as evidenced by the increased villus height and mRNA expression of tight junction related genes. Microbiological profile information revealed that MAG changed the gut microbiota, especially by elevating the abundances of Lactobacillus, Faecalibacterium, and Butyricicoccus. Moreover, non-targeted metabolomic analysis showed that MAG significantly promoted tryptophan metabolites, which was positively correlated with the MAG-enriched gut microbiota. The increased tryptophan metabolites could activate aryl hydrocarbon receptor (AhR) and relieved hepatic inflammation and immune response evidenced by the downregulated the gene expression levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the liver. The fecal microbiota transplantation (FMT) experiments further confirmed that the hepatoprotective effect is likely mediated by MAG-altered gut microbiota and their metabolites.ConclusionsMagnolol can be an outstanding supplement for the prevention and mitigation of FLHS in laying hens by positively regulating lipid synthesis and transport metabolism, improving the intestinal barrier function, and relieving hepatic inflammation by reshaping the gut microbiota and metabolite profiles through gut microbiota-indole metabolite-hepatic AhR crosstalk. These findings elucidate the mechanisms by which MAG alleviates FLHS and provide a promising method for preventing liver diseases by modulating gut microbiota and their metabolites.

Tetrahydropalmatine promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate atherosclerosis.

Atherosclerosis (AS) is a chronic progressive arterial disease that is associated with macrophage autophagy and AMP-activated protein kinase (AMPK)/mechanistic target of the rapamycin (mTOR) pathway. Tetrahydropalmatine (THP) can activate AMPK-dependent autophagy. We aim to study the mechanism of macrophage autophagy mediated by THP in the treatment of AS via the AMPK/mTOR pathway. High-fat diet apolipoprotein E-deficient mice and ox-LDL-induced RAW264.7 cells were used to mimic the AS model, then THP was administered. Cell viability was detected by MTT. Pathological aorta lesions were detected using Hematoxylin and Eosin, Masson, and oil red staining. Lipid metabolism indices and inflammatory factors were measured using ELISA. A transmission electron microscope was used to observe autophagosomes. Autophagy and AMPK/mTOR pathway protein expression was detected by immunofluorescence and Western blot. The AMPK inhibitor 9-β-d-Arabinofuranosyl Adenine (Ara-A) was used to validate the effect of THP. The mRNA expression of Beclin-1 and MCP-1 was detected by q-PCR. THP administration regulated lipid metabolism by lowering total cholesterol, triacylglycerol, low-density lipoprotein, and high-density lipoprotein levels, and suppressed aortic damage. THP suppressed aortic damage and regulated lipid metabolism by altering serum lipid levels. THP reduced inflammation and macrophage CD68 expression. Twenty μg/mL THP reduced cell viability. THP decreased cholesterol uptake and increased efflux, promoting autophagy. THP increased autophagosome number, LC3B expression, and autophagy markers p-AMPK/AMPK and LC3-II/LC3-I. THP also decreased p-mTOR/mTOR and P62. THP increased Beclin-1 mRNA expression and decreased MCP-1 mRNA expression. Ara-A reversed THP's effects. THP promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate AS.

Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

Early-life milk replacer feeding mediates lipid metabolism disorders induced by colonic microbiota and bile acid profiles to reduce body weight in goat model

BackgroundDysregulation of lipid metabolism and its consequences on growth performance in young ruminants have attracted attention, especially in the context of alternative feeding strategies. This study aims to elucidate the effects of milk replacer (MR) feeding on growth, lipid metabolism, colonic epithelial gene expression, colonic microbiota composition and systemic metabolism in goat kids compared to breast milk (BM) feeding, addressing a critical knowledge gap in early life nutrition.MethodsTen female goat kids were divided into 2 groups: those fed breast milk (BM group) and those fed a milk replacer (MR group). Over a period of 28 d, body weight was monitored and blood and tissue samples were collected for biochemical, transcriptomic and metabolomic analyses. Profiling of the colonial microbiota was performed using 16S rRNA gene sequencing. Intestinal microbiota transplantation (IMT) experiments in gnotobiotic mice were performed to validate causality.ResultsMR-fed pups exhibited reduced daily body-weight gain due to impaired lipid metabolism as evidenced by lower serum and liver total cholesterol (TC) and non-esterified fatty acid (NEFA) concentrations. Transcriptomic analysis of the colonic epithelium revealed upregulated genes involved in negative regulation of lipid metabolism, concomitant with microbiota shifts characterized by a decrease in Firmicutes and an increase in Actinobacteria. Specifically, genera such as Bifidobacterium and Prevotella were enriched in the MR group, while Clostridium and Faecalibacterium were depleted. Metabolomics analyses confirmed alterations in bile acid and fatty acid metabolic pathways. IMT experiments in mice recapitulated the metabolic phenotype observed in MR-fed goats, confirming the role of the microbiota in modulating host lipid metabolism.ConclusionsMilk replacer feeding in goat kids disrupts lipid metabolism and gut microbiota dynamics, resulting in reduced growth rates and metabolic alterations. These findings highlight the importance of early nutritional intervention on metabolic programming and suggest that modulation of the gut microbiota may be a target for improving growth and metabolic health in ruminants. This study contributes to the understanding of nutritional management strategies in livestock and their impact on animal health and productivity.

The influence of Helicobacter pylori infection on acute coronary syndrome and lipid metabolism in the Chinese ethnicity.

Acute coronary syndrome (ACS) patients frequently present a relatively high prevalence of Helicobacter pylori (H. pylori) infection. H. pylori was previously hypothesized to induce ACS through the regulation of lipid levels. However, the risk of H. pylori-induced ACS varies significantly among different ethnic groups, and the associations between H. pylori and lipid parameters remain unclear. This study aimed to systematically assess the risk of ACS in Chinese populations with H. pylori infection while also evaluating the effects of H. pylori on lipid parameters. A hospital-based case-control study involving 280 participants was conducted. Immunoblotting was used for the detection and genotyping of H. pylori. The associations between H. pylori and ACS, as well as lipid parameters, were analyzed via the chi-square test and a multiple logistic regression model. H. pylori infection significantly increased the risk of ACS among all participants (adjusted odds ratio (OR) = 4.04, 95% confidence interval (CI): 1.76-9.25, P < 0.05), with no associations with virulence factors (cytotoxin-associated gene A (CagA) or vacuole toxin geneA (VacA)). Subgroup analysis revealed a significant increase in the risk of ACS among the elderly population aged 56-64 years with H. pylori infection. Additionally, a substantial association was observed between H. pylori and acute myocardial infarction (AMI). No significant differences were found in lipid parameters, including low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and the LDL/HDL ratio, between individuals positive and negative for H. pylori infection. Similar results were observed between the ACS group and the control group. Our study has demonstrated for the first time that H. pylori does not significantly impact lipid metabolism but increases the risk of ACS fourfold in the Chinese population (OR = 4.04, 95% CI: 1.76-9.25). Furthermore, the virulence factors of H. pylori (CagA and VacA) may not be involved in the mechanisms by which they promote the development of ACS. This finding provides additional evidence for the association between H. pylori and ACS among different ethnic groups and refutes the biological mechanism by which H. pylori affects ACS through lipid metabolism regulation. Regular screening for H. pylori and eradication treatment in elderly individuals and those at high risk for ACS may be effective measures for reducing the incidence of ACS. Future research should include multicenter randomized controlled trials and explore host genetics and the effects of H. pylori on the gut microbiota as potential biological pathways linking H. pylori and ACS.

Multiomics analyses reveal high yield-related genes in the hypothalamic-pituitary-ovarian/liver axis of chicken

Egg production, regulated by multiple tissues, is among the most important economic traits in poultry. However, current research only focuses on the hypothalamic-pituitary-ovarian axis, ignoring the most important organ for substance metabolism in the body, the liver. Eggs are rich in lipids, proteins, and other nutrients, which are biosynthesized in the liver. Therefore, here the liver was included in the study of the hypothalamic-pituitary axis. This study used hypothalamus (HH_vs_LH), pituitary (HP_vs_LP), liver (HL_vs_LL), and ovary (HO_vs_LO) tissue samples from high- and low-laying Chengkou mountain chickens (CMCs) for epihistological, transcriptome and metabolomic analyses aimed at improving the reproductive performance of CMC. The results showed that the liver of the high-laying group was yellowish, the cell boundary was clear, and the lipid droplets were evenly distributed. The ovaries of the high-laying group had a complete sequence of hierarchical follicles, which were rich in yolk. In contrast, the ovaries of the low-laying group were atrophic, except for a few small yellow follicles, and numerous primordial follicles that remained. The transcriptome sequences yielded 167.11 Gb of clean data, containing 28,715 genes. Furthermore, 285, 822, 787, and 1,183 differentially expressed genes (DEGs) were identified in HH_vs_LH, HP_vs_LP, HL_vs_LL and HO_vs_LO and the DEGs significantly enriched 77, 163, 170, 171 pathways, respectively. Metabolome sequencing yielded 21,808 peaks containing 4,006 metabolites. The differential metabolite analysis yielded 343 and 682 significantly different metabolites (SDMs) that significantly enriched 136 and 87 pathways in the liver and ovaries, respectively. A combined analysis of the transcriptome and metabolome of the liver and ovaries identified “CYP51A1-4α-carboxy-stigmasta7, 24(24(1))-dien-3β-ol” and “ACSS1B-estrone 3-sulfate” and other multiple gene-metabolite pairs. The DEGs in the hypothalamus and pituitary mainly enriched signaling transduction. In contrast, the DEGs and SDMs in the liver and ovaries mainly enriched the substance metabolism pathways: “gap junction”, “extracellular matrix (ECM)-receptor interaction”, “Steroid biosynthesis”, and “Steroid hormone biosynthesis”. These results suggest that the hypothalamic-pituitary axis may affect egg production mainly by regulating lipid metabolism in the liver and ovaries.

Lactiplantibacillus plantarum P470 Isolated from Fermented Chinese Chives Has the Potential to Improve In Vitro the Intestinal Microbiota and Biological Activity in Feces of Coronary Heart Disease (CHD) Patients.

Traditional fermented foods are known to offer cardiovascular health benefits. However, the potential of fermented Chinese chives (FCC) in reducing coronary heart disease (CHD) remains unclear. This study employed anaerobic fermentation to investigate Lactiplantibacillus plantarum (L. plantarum) P470 from FCC. The results indicated that L. plantarum P470 enhanced hydroxyl radical scavenging and exhibited anti-inflammatory effects on RAW264.7 macrophages in the fecal fermentation supernatant of CHD patients. These effects were attributed to the modulation of gut microbiota and metabolites, including short-chain fatty acids (SCFAs). Specifically, L. plantarum P470 increased the abundance of Bacteroides and Lactobacillus while decreasing Escherichia-Shigella, Enterobacter, Veillonella, Eggerthella, and Helicobacter in CHD patient fecal samples. Furthermore, L. plantarum P470 regulated the biosynthesis of unsaturated fatty acids and linoleic acid metabolism. These findings suggest that L. plantarum P470 from FCC can improve the fecal physiological status in patients with CHD by modulating intestinal microbiota, promoting SCFA production, and regulating lipid metabolism.

HuR/miR-124-3p/VDR complex bridges lipid metabolism and tumor development in colorectal cancer.

Maintaining a balanced lipid status to prevent lipotoxicity is of paramount importance in various tumors, including colorectal cancer (CRC). HuR, an RNA-binding protein family member, exhibits high expression in many cancers possibly because it regulates cell proliferation, migration, invasion, and lipid metabolism. However, the role of HuR in the regulation of abnormal lipid metabolism in CRC remains unknown. We found that HuR promotes vitamin D receptor (VDR) expression to ensure lipid homeostasis by increasing Triglyceride (TG) and Total Cholesterol (TC) levels in CRC, thus confirming the direct binding of an overexpressed HuR to the CDS and 3'-UTR of Vdr, enhancing its expression. Concurrently, HuR can indirectly affect VDR expression by inhibiting miR-124-3p. HuR can suppress the expression of miR-124-3p, which binds to the 3'-UTR of Vdr, thereby reducing VDR expression. Additionally, a xenograft model demonstrated that targeting HuR inhibits VDR expression, blocking TG and TC formation, and hence mitigating CRC growth. Our findings suggest a regulatory relationship among HuR, miR-124-3p, and VDR in CRC. We propose that the HuR/miR-124-3p/VDR complex governs lipid homeostasis by impacting TG and TC formation in CRC, offering a potential therapeutic target for CRC prevention and treatment.

Investigating Ethanolic Extract from Acehnese Lime (Citrus aurantifolia) Peel as Potential Anti-Hypercholesterolemia Agent

Lime peels are rich in flavonoids, alkaloids, phenols, saponins, and tannins, exhibiting antibacterial, antioxidant, anti-inflammatory, anti-hypertensive, and anti-hypercholesterolemia properties. However, the specific active constituents of Acehnese lime peels and their impact on anti-hypercholesterolemia effects remain undisclosed. This present investigation aims to identify the active compounds in the ethanolic extract of locally obtained Acehnese lime (Citrus aurantifolia (Christm.) Swingle) peels and assess their potential as inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG Co-A) reductase using in-silico approach. The composition of the ethanolic extract Acehnese lime peel was determined through phytochemical analysis, 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, gas chromatography-mass spectrometry (GC-MS) analysis, and predictions of biological activity, while the biological activities of their compounds were evaluated through molecular docking. Phytochemicals revealed the presence of phenolics, flavonoids, tannins, saponins, and terpenoids in the ethanolic extract of local Aceh lime peel. The total phenolic and flavonoid contents were 29.992 ± 0.274 mg gallic acid equivalents (GAE)/g extract and 5.983 ± 0.017 mg quercetin equivalents (QE)/g extract, respectively. The anti-oxidant activity was notably strong with an IC50 value of 49.51 ppm. GC-MS analysis identified 6-methoxychroman-2-one (27.64%) as the primary component in ethanolic extract Acehnese lime peel, along with neric acid (C13H22O2) known as a regulator of lipid metabolism (Pa: 0.941). In-silicoinvestigations indicated that pterin-6-carboxylic acid (-7.8 kcal/mol) exhibited a higher binding free energy for the PCSK9 receptor compared to simvastatin (-7.6 kcal/mol), whereas the active compound (R)-9-(2,3-dihydroxy-3-methylbutoxy)-4- exhibited the highest binding capacity for HMG Co-A reductase (-6.9 kcal/mol) compared to other compounds. These findings suggest that the ethanolic extract of Acehnese lime peels could serve as an effective inhibitor of PCSK9 and HMG Co-A reductase, highlighting its potential as a novel anti-hypercholesterolemia agent. Doi: 10.28991/HEF-2024-05-03-04 Full Text: PDF

Oligomeric procyanidins combined with Parabacteroides distasonis ameliorate high-fat diet-induced atherosclerosis by regulating lipid metabolism, inflammation reaction and bile acid metabolism in ApoE−/− mice

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases. Hence, the prevention and treatment strategies of AS have attracted great research attention. As a potential probiotic, Pararabacteroides distasonis has a positive regulatory effect on lipid metabolism and bile acids (BAs) profile. Oligomeric procyanidins have been confirmed to be conducive to the prevention and treatment of AS, whose anti-atherosclerotic effect may be associated with the promotion of gut probiotics. However, it remains unclear whether and how oligomeric procyanidins and P. distasonis combined (PPC) treatment can effectively alleviate high-fat diet (HFD)-induced AS. In this study, PPC treatment was found to significantly decrease atherosclerotic lesion, as well as alleviate the lipid metabolism disorder, inflammation and oxidative stress injury in ApoE−/− mice. Surprisingly, targeted metabolomics demonstrated that PPC intervention altered the BA profile in mice by regulating the ratio of secondary BAs to primary BAs, and increased fecal BAs excretion. Further, quantitative polymerase chain reaction (qPCR) analysis showed that PPC intervention facilitated reverse cholesterol transport by upregulating Srb1 expression; In addition, PPC intervention promoted BA synthesis from cholesterol in liver by upregulating Cyp7a1 expression via suppression of the farnesoid X receptor (FXR) pathway, thus exhibiting a significant serum cholesterol-lowering effect. In summary, PPC attenuated HFD-induced AS in ApoE−/− mice, which provides new insights into the design of novel and efficient anti-atherosclerotic strategies to prevent AS based on probiotics and prebiotics.

Sirt1 Mitigates Hepatic Lipotoxic Injury Induced by High-Fat-Diet in Fish Through Ire1α Deacetylation

BackgroundSilent information regulator protein 1 (Sirt1) is crucial in regulating lipid metabolism, but its specific role and mechanism in fish hepatic lipotoxic injury remain undefined. ObjectivesThis study aimed to elucidate the regulatory role of Sirt1 and the underlying mechanisms in dietary lipid-induced hepatic lipotoxic injury in a marine teleost black seabream. MethodsBlack seabream were fed a control diet (12% lipid level), high-fat diet (HFD) [18% lipid level, oleic acid (OA)-rich], or HFD supplemented with 0.25%, 0.50%, or 1.00% resveratrol (RSV) for 8 wk. The cultured hepatocytes were stimulated by OA (200 μM), OA supplemented with RSV (20 μM), or transfection with sirt1-small interfering RNA (sisirt1). Biochemical indices, gene expression (qPCR), histology, transmission electron microscope, immunofluorescence, Western blot, flow cytometry, and immunoprecipitation assays were conducted to evaluate hepatic lipid deposition, lipid metabolism, endoplasmic reticulum stress, inflammation and apoptosis, and determine protein interactions between Sirt1 and Ire1α. ResultsIn vivo, RSV supplementation increased mRNA and protein expression levels of sirt1 (236.2% ± 16.1% and 53.1% ± 14.3%) and downregulated the mRNA and phosphorylated protein expression levels of ire1α/Ire1α (46.0% ± 7.6% and 38.6% ± 7.0%), jnk/Jnk (57.6% ± 7.3% and 122.1%), and nuclear factor κ B (nf-κb/Nf-κb) p65 (41.7% ± 7.1% and 24.6% ± 0.8%) compared with the HFD group. Similar patterns were found in the in vitro experiments; however, after knockdown of sirt1, although the cells were incubated with RSV, the expression levels of ire1α/ Ire1α, jnk/Jnk, and nf-κb/Nf-κb p65 showed no significant differences compared with the OA treatment. Moreover, we found that mutation of K61 to arginine to mimic Ire1α deacetylation confers protection against Ire1α-mediated OA-rich HFD-induced inflammation and apoptosis. ConclusionsThe findings revealed that Sirt1 protects against OA-rich HFD-induced hepatic lipotoxic injury via the deacetylation of Ire1α on K61, hence reducing Ire1α autophosphorylation level, and suppressing Jnk and Nf-κb p65 activation. This mechanism is elucidated for the first time in fish.

Tangerine Peel-Derived Exosome-Like Nanovesicles Alleviate Hepatic Steatosis Induced by Type 2 Diabetes: Evidenced by Regulating Lipid Metabolism and Intestinal Microflora.

Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden, exhibiting a strong correlation with insulin resistance, obesity, and type 2 diabetes (T2DM). Despite the severity of hepatic steatosis in T2DM patients, no specific drugs have been approved for clinical treatment of the disease. Tangerine peel is one kind of popular functional food and reported to possess hypoglycemic and lipid-lowering potential. In this study, we investigated the effects of Tangerine-peel-derived exosome-like nanovesicles (TNVs) on hepatic lipotoxicity associated with T2DM. The TNVs was prepared by differential centrifugation of the aqueous extract of Tangerine and chemical properties were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and LC-MS/MS. The hypoglycemic and lipid-lowering potential of TNVs were possessed by biochemical measurement, RT-PCR, 16S rRNA sequencing, GC/MS, UHPLC-MS/MS, in vivo small animal imaging assay and HE staining. Subsequently, effects of TNVs on lipid accumulation and glycolysis were investigated on 3T3-L1 and AML-12 cells. TNVs significantly inhibited insulin resistance, reduced hepatic lipid accumulation, facilitate intestinal mucosal repair, rescued gut microbiota dysbiosis, regulated colonic SCFA and liver bile acid metabolism in db/db mice. Furthermore, TNVs restored the expression of key genes in glucose and lipid metabolism (ACC, AMPK, CD36, LXRα, PPAR-γ, SREBP-1) while activating the expression of genes related to glycolysis (G6Pase, GLUT2, PCK1, PEPCK) in db/db mice. Further cell-based mechanistic studies revealed that TNVs reduced lipid accumulation in 3T3-L1 and AML-12 cells via regulation of glucose and lipid metabolism-related genes (UCP1, FGFR4, PRDM16, PGC-1α, Tmem26, Cpt1, Cpt2 and PPAR-α). We for the first time demonstrated that TNVs could significantly improve glucose and lipid metabolism via activating the expression of genes related to fatty acid β-oxidation and glycolysis.

Integrated lipidomics and network pharmacology analysis to determine how Gu Fu Sheng Capsule improves lipid metabolism in rats with steroid-induced osteonecrosis of the femoral head

BackgroundSteroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent refractory condition in orthopedics, often causing high disability rates. Gu Fu Sheng Capsule (GFSC) is commonly used to treat SONFH during the early and intermediate stages. However, the precise underlying mechanism of action of GFSC remains elusive. ObjectiveTo elucidate the mechanism through which GFSC improves lipid metabolism in rats with SONFH. MethodsA rat model of SONFH was established by administering methylprednisolone and lipopolysaccharide. Micro-computed tomography assessed femoral head effects, while hematoxylin–eosin staining examined femoral head tissues. Pathological changes were evaluated using an automated biochemical analyzer to measure changes in serum lipid levels. Besides, quantitative lipidomics and network pharmacology were used to determine how GFSC impacts SONFH. qRT-PCR and Western blotting were performed to assess mRNA and protein expression levels of key targets. ResultsGFSC can enhance bone density and prevents surface collapse of the femoral head, improve hollow bone lacuna density, reduce adipocyte infiltration, minimize osteocyte cavities, regulate the serum lipid levels and enhance lipid metabolism in SONFH rats. Moreover, integrated lipidomics and network pharmacology suggested that GFSC affects lipid metabolism-related genes by regulating nine targets, thereby influencing four metabolites and two metabolic pathways, which may mainly be due to components in GFSC such as quercetin, tanshinone iia, berberine. Western blotting and qRT-PCR data highlighted that GFSC improves lipid metabolism by regulating TP53, HSP90AA1, and ESR1. ConclusionGFSC effectively retards SONFH progression, potentially attributed to its ability to regulate lipid metabolism.

Nutritional condition drives spatial variation in physiology of Antarctic lipid-storing copepods.

Lipid-rich copepods form an essential link between primary producers and higher trophic levels in high-latitude oceans. These zooplankton can take advantage of ephemeral phytoplankton blooms to fuel development and reproduction. However, we have limited understanding of how the physiological condition of these animals varies in relation to environmental factors such as food availability. Due to high advection, it is likely that physiological plasticity, rather than local adaptation, is primarily responsible for physiological differences within a region. We use transcriptomics and other physiological metrics to understand how two species of copepods (Calanoides acutus and Calanus propinquus) vary across environmental gradients along the West Antarctic Peninsula. For the primarily herbivorous C. acutus, physiological separation between sampling locations appears to be driven by feeding status, and gene expression differences indicate differential expression of genes regulating lipid metabolism, reproduction, aerobic metabolism, and protein translation. For the more omnivorous C. propinquus, physiology and gene expression did not segregate as clearly by location, showed minimal signs of food deprivation at any location, and had a weaker relationship with chlorophyll compared to C. acutus. By comparing these results with concurrent starvation experiments, we find that spatial variation in gene expression reflects short-term differences in food availability (particularly for C. acutus), and we identify genes whose expression indicates recent feeding status. Further examination of the relationships between food availability, copepod physiology, and population dynamics will ultimately improve our capacity to predict how copepod populations will respond to rapidly changing environmental conditions in the West Antarctic Peninsula ecosystem.

Specific microRNA Profile Associated with Inflammation and Lipid Metabolism for Stratifying Allergic Asthma Severity.

The mechanisms underlying severe allergic asthma are complex and unknown, meaning it is a challenge to provide the most appropriate treatment. This study aimed to identify novel biomarkers for stratifying allergic asthmatic patients according to severity, and to uncover the biological mechanisms that lead to the development of the severe uncontrolled phenotype. By using miRNA PCR panels, we analyzed the expression of 752 miRNAs in serum samples from control subjects (n = 15) and mild (n = 11) and severe uncontrolled (n = 10) allergic asthmatic patients. We identified 40 differentially expressed miRNAs between severe uncontrolled and mild allergic asthmatic patients. Functional enrichment analysis revealed signatures related to inflammation, angiogenesis, lipid metabolism and mRNA regulation. A random forest classifier trained with DE miRNAs achieved a high accuracy of 97% for severe uncontrolled patient stratification. Validation of the identified biomarkers was performed on a subset of allergic asthmatic patients from the CAMP cohort at Brigham and Women's Hospital, Harvard Medical School. Four of these miRNAs (hsa-miR-99b-5p, hsa-miR-451a, hsa-miR-326 and hsa-miR-505-3p) were validated, pointing towards their potential as biomarkers for stratifying allergic asthmatic patients by severity and providing insights into severe uncontrolled asthma molecular pathways.