Choline Metabolism Research Articles

Choline kinase alpha genotype is related to hippocampal brain volume and cognition in postmenopausal women

This study examined how single nucleotide polymorphisms (SNPs) related to choline synthesis and metabolism, processes largely regulated by estrogen, influenced hippocampal volume and neuropsychological function following menopause. We investigated the effect of choline kinase alpha (CHKA) genotype on brain volume and neuropsychological performance in postmenopausal women. The effect alleles of certain CHKA SNPs (rs6591331 T, rs10791957 A) are associated with varied responses to choline deficiency and delegation of choline to physiological pathways. The presence of these alleles was hypothesized to correlate with worse cognitive performance in women after menopause. Results from structural MRI scans revealed larger right hippocampal volumes in subjects with a T/T CHKA rs6591331 genotype compared to A/A subjects. Delayed memory scores from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were lower in subjects with T/T genotypes compared to those with the A/T genotype and the A/A genotype. Based on these findings, we proposed a CHKA-dependent mechanism present within the brain to compensate for the decreased estrogen and biosynthesized choline associated with menopause.

Investigation of metabolite alterations in thekidneys of methionine-choline-deficient mouse by mass spectrometry imaging.

Methionine and choline both are essential nutrients which are needed for methyl group metabolism. Amethionine-choline-deficient (MCD) diet leads to pathological changes in the kidney. The mechanism of theMCD diet is complex, and fundamental research is still required to provide a better understanding of the driving forces behind it. We evaluated the regional effects of the MCD diet on the metabolites of mouse kidney tissue using desorption electrospray ionization mass spectrometry imaging technology. A total of 20, 17, and 13 metabolites were significantly changed in the cortex, outer medulla, and inner medulla, respectively, of the mouse kidney tissue after the administration of theMCD diet. Among the discriminating metabolites, only three metabolites (guanidoacetic acid, serine, and nicotinamide riboside) were significantly increased, and all the other metabolites showed asignificant decrease. The results showed that there were significant region-specific changes in the serine metabolism, carnitine metabolism, choline metabolism, and arginine metabolism. This study presents unique regional metabolic data, providing a more comprehensive understanding of the molecular characteristics of theMCD diet in the kidney.

Reduced GABA concentration in patients with white matter hyperintensities.

To investigate potential alterations of white matter hyperintensities (WMHs) on J-edited MR spectroscopy (MRS) measures of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA). Twenty-four WMHs patients and 20 healthy controls (HCs) were recruited to undergo magnetic resonance spectroscopy (MRS) scan at 3T from voxels in left centrum semiovale white matter, using the MEGA point resolved spectroscopy (MEGA-PRESS) technique with the MATLAB-based Gannet tool to estimate GABA+ co-edited macromolecule (GABA+) levels and using Tarquin software to estimate levels of glutamate + glutamine (Glx), total N-acetylaspartate (tNAA), total choline (tCho), and total creatine (tCr). Independent t-tests or Mann-Whitney U-tests were used to test group differences between WMHs and HCs. Additionally, WMHs patients were divided into mild and moderate-severe WMHs subgroup according to the Fazekas scale. Analysis of variance (ANOVA) and post-hoc tests were used among WMHs subgroups and HCs. We found there was a significant reduction in GABA+ levels (p = 0.018) in WMHs patients compared with healthy controls. In subgroup analyses, there was also a significant reduction of GABA+ levels in moderate-severe WMHs subgroup (p = 0.037) and mild WMHs subgroup (p = 0.047) when compared to HCs. Besides, the moderate-severe WMHs subgroup had significantly higher levels of tCho compared with healthy controls (p = 0.019). In conclusion, reduced GABA+ levels in WMHs patients and elevated tCho levels in moderate-severe WMHs were observed when compared with HCs. These results demonstrate that abnormalities of the GABAergic system and choline metabolism may contribute to the pathogenesis of WMHs.

Action Mechanisms of Metformin Combined with Exenatide and Metformin Only in the Treatment of PCOS in Obese Patients.

Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of reproductive age, whose clinical characteristics are hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovary, often accompanied by insulin resistance (IR) and metabolic abnormalities. Glucagon-like peptide (GLP)-1 receptor agonists (GLP-1Ra), such as exenatide, can bind to specific receptors on tissues such as the ovaries to improve the clinical phenotype of PCOS, while insulin-sensitizing agents, such as metformin, can also benefit to metabolic abnormalities in PCOS. Liquid chromatography-mass spectrometry (LC/MS) metabolomics revealed differences between the mechanisms of exenatide and metformin treatment of PCOS to some extent. In this study, 50 obese subjects with PCOS were randomly divided into the exenatide combined with metformin group (COM group, n = 28) and the metformin group (MF group, n = 22) for 12-week treatment. Before and after, serum samples were subjected to LC/MS analysis. After treatment, there were 153 named differential metabolites in the COM group and 99 in the MF group. Most phosphatidylcholines (PC) and deoxycholic acid 3-glucuronide (DA3G) were significantly upregulated, while most glycerophosphoethanolamine (PE-NMe2), glycerophosphocholine (GPC), and threonine were downregulated in both groups. Only the decrease of neuromedin B, glutamate, and glutamyl groups and the increase of chenodeoxycholic acid sulfate docosadienoate (22: 2n6), and prostaglandin E2 have been observed in the COM group. In addition, salicylic acid and spisulosine increased and decanoylcarnitine decreased in the MF group. Both groups were enriched in glycerophospholipid, choline, and sphingolipid metabolism, while the COM group was especially superior in the glutamine and glutamate, bile secretion, and amino acid metabolism. Compared with metformin alone in the treatment of PCOS, the differential metabolites of the exenatide combined with metformin group are more extensive. The COM group may act on the hypothalamic-pituitary-gonadal axis (HPO) and its bypass, regulate multiple metabolism pathways such as phospholipids, amino acids, fatty acids, carnitine, bile acids, and glucose directly or indirectly in obese PCOS patients.

Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by 1 H HR-MAS NMR.

In this study, we investigated the metabolic signatures of different mitochondrial defects (two different complex I and complex V, and the one MDH2 defect) in human skin fibroblasts (HSF). We hypothesized that using a selective culture medium would cause defect specific adaptation of the metabolome and further our understanding of the biochemical implications for the studied defects. All cells were cultivated under galactose stress condition and compared to glucose-based cell culture condition. We investigated the bioenergetic profile using Seahorse XFe96 cell analyzer and assessed the extracellular metabolic footprints and the intracellular metabolic fingerprints using NMR. The galactose-based culture condition forced a bioenergetic switch from a glycolytic to an oxidative state in all cell lines which improved overall separation of controls from the different defect groups. The extracellular metabolome was discriminative for separating controls from defects but not the specific defects, whereas the intracellular metabolome suggests CI and CV changes and revealed clear MDH2 defect-specific changes in metabolites associated with the TCA cycle, malate aspartate shuttle, and the choline metabolism, which are pronounced under galactose condition.

Sperm-borne tsRNAs and miRNAs analysis in relation to dairy cattle fertility

Sperm small non-coding RNAs (sncRNAs), such as microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNAs), have been found to have implications for male fertility and play a role in the intergenerational transmission of specific phenotypes by influencing the early embryo's physiological processes in various animal species. This study postulates that there exists a correlation between sperm small non-coding RNAs (sncRNAs) and bull fertility, which in turn can influence the fertility of offspring through the modulation of early embryo development. To investigate this hypothesis, we generated comparative libraries of sperm sncRNAs from sires exhibiting high (n = 3) versus low bull fertility (n = 3), as well as high (n = 3) versus low daughter fertility (n = 3), as determined by the industry-standard Bull fertility index and Daughter fertility index. In total, 12 tsRNAs carried by sperm (11 down-regulated and 1 up-regulated) were found to be associated with bull fertility, while 19 tsRNAs (11 down-regulated and 8 up-regulated) were found to be associated with daughter fertility (q < 0.05, Log2foldchange>±1.5, base mean > 50). Notably, tRX-Glu–NNN–3811 exhibited potential as a biomarker for predicting fertility in both male and female dairy cattle. Moreover, a total of six miRNAs sperm-borne (two up-regulated and four down-regulated) and 35 miRNAs (27 up-regulated and eight down-regulated) exhibited a significant correlation with both bull fertility and daughter fertility individually (p < 0.05, base mean > 50, log2foldchange>±1.5), two microRNAs, namely miR-2385-5p (down-regulated) and miR-98 (up-regulated), exhibit a significant association (p < 0.05, base mean > 50, log2foldchange>±1.5) with the fertility of both bulls and daughter. The targets of these two microRNAs were subsequently identified and integrated with the transcriptomic database of the embryonic cells at the two-cell stage, which is known to be indicative of embryonic competence. The KEGG analysis revealed a potential correlation between these targets and choline metabolism, a crucial factor in embryonic epigenetic programming.In summary, the findings of this study indicate that sperm-borne small non-coding RNAs (sncRNAs) hold promise as biomarkers for predicting and enhancing fertility in dairy cattle. Furthermore, it is plausible that these sncRNAs may exert their effects on daughter fertility by targeting genes in the early embryo.

Integrative transcriptome and metabolome analysis of fluoride exposure induced developmental neurotoxicity in mouse brain

Fluoride could cause developmental neurotoxicity and significantly affect the intelligence quotient (IQ) of children. However, the systematic mechanism of neuronal damage caused by excessive fluoride administration in offspring is largely unknown. Here, we present a comprehensive integrative transcriptome and metabolome analysis to study the mechanism of developmental neurotoxicity caused by chronic fluoride exposure. Comparing the different doses of fluoride treatments in two generations revealed the exclusive signature of metabolism pathways and gene expression profiles. In particular, neuronal development and synaptic ion transport are significantly altered at the gene expression and metabolite accumulation levels for both generations, which could act as messengers and enhancers of fluoride-induced systemic neuronal injury. Choline and arachidonic acid metabolism, which highlighted in the integrative analysis, exhibited different regulatory patterns between the two generations, particularly for synaptic vesicle formation and inflammatory factor transport. It may suggest that choline and arachidonic acid metabolism play important roles in developmental neurotoxic responses for offspring mice. Our study provides comprehensive insights into the metabolomic and transcriptomic regulation of fluoride stress responses in the mechanistic explanation of fluoride-induced developmental neurotoxicity.

Integration of pharmacodynamics, metabolomics and network pharmacology to elucidate the effect of Prunella vulgaris seed oil in the treatment of hyperlipidemia

To investigate the lipid-lowering activity of PVSO (a natural oil derived from the mature seeds of Prunella vulgaris L.), supercritical CO2 extraction technology was used to extract, and the components were characterized using GC–MS/MS and LC-MS/MS techniques. The lipid-lowering activity of PVSO was evaluated in vitro and in vivo. The results indicated that the supercritical CO2 extraction rate of PVSO was 16.63 %, and the ratio of linolenic acid to linoleic acid was 3:1. In addition, PVSO also contains bioactive components such as phenols, terpenes, flavonoids, and squalene. In vitro experiments showed that PVSO has a strong inhibitory effect on porcine pancreatic lipase, cholesterol esterase, and cholesterol micellization in a significant dose-dependent manner. In vivo experiments showed that PVSO (500 and 800 mg/kg) intervention markedly attenuated body-weight gain, liver weights, hepatic steatosis, oxidative stress biomarkers, and dyslipidemia induced by HFD (p < 0.05). Serum metabolomics studies revealed that 29 endogenous metabolites were significantly altered by HFD and recovered following intervention with PVSO (p < 0.05). PVSO suppressed hyperlipidemia mainly by regulating oxidative stress, choline metabolism, glycine, serine and threonine metabolism, and cholesterol metabolism. Combining metabolomics and network pharmacology analysis, 17 intersection targets, 21 GO and 6 KEGG pathways were obtained. Molecular docking showed that ACHE, CPT1A, HMGCR, LYPLA1, and PLD2 were the key targets of PVSO against hyperlipidemia. In summary, PVSO might be a potential active resource to prevent oxidative stress and lipid metabolism disorders in HFD-induced hyperlipidemia.

Liriodendrin exerts protective effects against chronic endometritis in rats by modulating gut microbiota composition and the arginine/nitric oxide metabolic pathway

BackgroundChronic endometritis (CE), a gynecological disease, is characterized by inflammation. Liriodendrin is reported to exhibit anti-inflammatory properties. However, the therapeutic effects of liriodendrin on CE and the underlying molecular mechanisms have not been elucidated. This study aimed to investigate the therapeutic effects of liriodendrin on CE in rats and the underlying mechanisms. MethodsA CE rat model was established and administered with liriodendrin for 21 days. The serum levels of inflammatory cytokines were examined using enzyme-linked immunosorbent assay. The uterine mRNA levels of cytokines were examined using quantitative real-time polymerase chain reaction analysis. The activation of the Toll-like receptor 4 (TLR4)/NF-κB pathway was investigated using western blotting analysis. The effects of liriodendrin on intestinal flora and serum metabolites were examined using 16S rRNA sequencing and untargeted serum metabolomics, respectively. The protein and mRNA levels of arginase-2 (Arg-2) and the nitric oxide (NO) metabolic pathway-related factors were assessed. Molecular docking was performed to explore the interaction between liriodendrin and Arg-2. ResultsLiriodendrin alleviated the CE-induced pathological changes in the uterus, modulated the serum levels of inflammatory cytokines, and downregulated the mRNA and protein levels of TLR4/NF-κB pathway-related factors. Treatment with liriodendrin mitigated the CE-induced upregulation of Firmicutes/Bacteroidetes ratio and Lachnospiraceae abundance and downregulation of Ruminococcaceae abundance. Serum metabolomic analysis revealed that liriodendrin regulated the biosynthesis of choline metabolism pathway-related factors. Liriodendrin suppressed the CE-induced upregulation of Arg-2 and downregulation of inducible nitric oxide synthase (iNOS) expression, and NO levels by directly binding to the amino acid residues of Arg-2 through hydroxyl bonds. ConclusionsLiriodendrin exerted therapeutic effects on CE in rats through the alleviation of inflammation by modulating the gut microbiota structure, directly downregulating Arg-2, and regulating the arginine/NO metabolic pathway.

A single shell protein plays a major role in choline transport across the shell of the choline utilization microcompartment of Escherichia coli 536.

Bacterial microcompartments (MCPs) are widespread protein-based organelles that play important roles in the global carbon cycle and in the physiology of diverse bacteria, including a number of pathogens. MCPs consist of metabolic enzymes encapsulated within a protein shell. The main roles of MCPs are to concentrate enzymes together with their substrates (to increase reaction rates) and to sequester harmful metabolic intermediates. Prior studies indicate that MCPs have a selectively permeable protein shell, but the mechanisms that allow selective transport across the shell are not fully understood. Here we examine transport across the shell of the choline utilization (Cut) MCP of Escherichia coli 536, which has not been studied before. The shell of the Cut MCP is unusual in consisting of one pentameric and four hexameric bacterial microcompartment (BMC) domain proteins. It lacks trimeric shell proteins, which are thought to be required for the transport of larger substrates and enzymatic cofactors. In addition, its four hexameric BMC domain proteins are very similar in amino acid sequence. This raises questions about how the Cut MCP mediates the selective transport of the substrate, products and cofactors of choline metabolism. In this report, site-directed mutagenesis is used to modify the central pores (the main transport channels) of all four Cut BMC hexamers to assess their transport roles. Our findings indicate that a single shell protein, CmcB, plays the major role in choline transport across the shell of the Cut MCP and that the electrostatic properties of the CmcB pore also impact choline transport. The implications of these findings with regard to the higher-order structure of MCPs are discussed.

Partially Alternative Feeding with Fermented Distillers' Grains Modulates Gastrointestinal Flora and Metabolic Profile in Guanling Cattle.

Fermented distillers' grains (FDG) are commonly used to enhance the health and metabolic processes of livestock and poultry by regulating the composition and activity of the intestinal microbiota. Nevertheless, there is a scarcity of research on the effects of the FDG diet on the gastrointestinal microbiota and its metabolites in cattle. This study examines the impact of FDG dietary supplements on the gastrointestinal flora and metabolic profile of Guanling cattle. Eighteen cattle were randomly assigned to three treatment groups with six replicates per group. The treatments included a basal diet (BD), a 15% concentrate replaced by FDG (15% FDG) in the basal diet, and a 30% concentrate replaced by FDG (30% FDG) in the basal diet. Each group was fed for a duration of 60 days. At the conclusion of the experimental period, three cattle were randomly chosen from each group for slaughter and the microbial community structure and metabolic mapping of their abomasal and cecal contents were analyzed, utilizing 16S rDNA sequencing and LC-MS technology, respectively. At the phylum level, there was a significant increase in Bacteroidetes in both the abomasum and cecum for the 30%FDG group (p < 0.05). Additionally, there was a significant reduction in potential pathogenic bacteria such as Spirochetes and Proteobacteria for both the 15%FDG and 30%FDG groups (p < 0.05). At the genus level, there was a significant increase (p < 0.05) in Ruminococcaceae_UCG-010, Prevotellaceae_UCG-001, and Ruminococcaceae_UCG-005 fiber degradation bacteria. Non-target metabolomics analysis indicated that the FDG diet significantly impacted primary bile acid biosynthesis, bile secretion, choline metabolism in cancer, and other metabolic pathways (p < 0.05). There is a noteworthy correlation between the diverse bacterial genera and metabolites found in the abomasal and cecal contents of Guanling cattle, as demonstrated by correlation analysis. In conclusion, our findings suggest that partially substituting FDG for conventional feed leads to beneficial effects on both the structure of the gastrointestinal microbial community and the metabolism of its contents in Guanling cattle. These findings offer a scientific point of reference for the further use of FDG as a cattle feed resource.

Choline metabolism and its implications in cancer.

Choline, a quintessential quaternary ammonium compound, plays a cardinal role in several pivotal biological mechanisms, chiefly in safeguarding cell membrane integrity, orchestrating methylation reactions, and synthesizing vital neurotransmitters. This systematic review meticulously dissects the complex interplay between choline metabolism and its profound implications in oncology. The exposition is stratified into three salient dimensions: Initially, we delve into the intricacies of choline metabolism, accentuating its indispensability in cellular physiology, the enzymatic labyrinth governing its flux, and the pivotal cellular import mechanisms. Subsequently, we elucidate the contemporary comprehension of choline metabolism in the cancer paradigm, traversing its influence from inception to the intricate metamorphosis during oncogenic progression, further compounded by dysregulated enzyme activities and aberrant signaling cascades. Conclusively, we illuminate the burgeoning potential of choline-centric metabolic imaging modalities, notably magnetic resonance spectroscopy (MRS) and positron emission tomography (PET), as avant-garde tools for cancer diagnostics and therapeutic trajectory monitoring. Synoptically, the nuanced perturbations in choline metabolism in neoplastic entities unfurl critical insights, potentially heralding paradigm shifts in diagnostic and therapeutic oncological stratagems. A deeper foray into this realm is anticipated to fortify our molecular understanding and refine intervention modalities in cancer theranostics.

Functional characterization of Clonorchis sinensis choline transporter.

Clonorchis sinensis is commonly found in East Asian countries. Clonorchiasis is prevalent in these countries and can lead to various clinical symptoms. In this study, we used overlap extension polymerase chain reaction (PCR) and the Xenopus laevis oocyte expression system to isolate a cDNA encoding the choline transporter of C. sinensis (CsChT). We subsequently characterized recombinant CsChT. Expression of CsChT in X. laevis oocytes enabled efficient transport of radiolabeled choline, with no detectable uptake of arginine, α-ketoglutarate, p-aminohippurate, taurocholate, and estrone sulfate. Influx and efflux experiments showed that CsChT-mediated choline uptake was time- and sodium-dependent, with no exchange properties. Concentration-dependent analyses of revealed saturable kinetics consistent with the Michaelis-Menten equation, while nonlinear regression analyses revealed a Km value of 8.3 μM and a Vmax of 61.0 pmol/oocyte/h. These findings contribute to widen our understanding of CsChT transport properties and the cascade of choline metabolisms within C. sinensis.

Choline metabolites and incident cardiovascular disease in a prospective cohort of adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study

BackgroundThe potential role for choline metabolite trimethylamine N-oxide (TMAO) in cardiovascular disease (CVD) has garnered much attention, but there have been limited data from diverse population-based cohorts. Furthermore, few studies have included circulating choline and betaine, which can serve as precursors to TMAO and may independently influence CVD. ObjectiveWe quantified prospective associations between 3 choline metabolites and 19-y incident CVD in a population-based cohort and tested effect modification of metabolite–CVD associations by kidney function. MethodsData were from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort with recruitment from 4 US urban centers (year 0: 1985–1986, n = 5115, ages 18–30). The analytic sample included 3444 White and Black males and females, aged 33 to 45, who attended the year 15 follow-up exam and did not have prevalent CVD. TMAO, choline, and betaine were quantitated from stored plasma (−70°C) using liquid-chromatography mass-spectrometry. Nineteen-year incident CVD events (n = 221), including coronary heart disease and stroke, were identified through adjudicated hospitalization records and linkage with the National Death Register. ResultsPlasma choline was positively associated with CVD in Cox proportional hazards regression analysis adjusted for demographics, health behaviors, CVD risk factors, and metabolites (hazard ratio: 1.24; 95% CI: 1.09, 1.40 per standard deviation-unit choline). TMAO and betaine were not associated with CVD in an identically adjusted analysis. There was statistical evidence for effect modification by kidney function with CVD positively associated with TMAO and negatively associated with betaine at lower values of estimated glomerular filtration rate (interaction P values: 0.0046 and 0.020, respectively). ConclusionsOur findings are consistent with a positive association between plasma choline and incident CVD. Among participants with lower kidney function, TMAO was positively, and betaine negatively, associated with CVD. These results further our understanding of the potential role for choline metabolism on CVD risk.

CDP-choline modulates cholinergic signaling and gut microbiota to alleviate DSS-induced inflammatory bowel disease

Inflammatory bowel diseases (IBD) represent chronic gastrointestinal inflammatory disorders characterized by a complex and underexplored pathogenic mechanism. Previous research has revealed that IBD patients often have a deficiency of choline and its metabolites, including acetylcholine (ACh) and phosphatidylcholine (PC), within the colon. However, a comprehensive study linking these three substances and their mechanistic implications in IBD remains lacking. This study aimed to investigate the efficacy and underlying mechanism of cytidine diphosphate (CDP)-choline (citicoline), an intermediate product of choline metabolism, in a mouse model of IBD induced by dextran sulfate sodium salt (DSS). The results demonstrated that CDP-choline effectively alleviated colonic inflammation and deficiencies in choline, ACh, and PC by increasing the raw material. Further detection showed that CDP-choline also increased the ACh content by altering the expression of high-affinity choline transporter (ChT1) and acetylcholinesterase (AChE) in DSS-induced mice colon. Moreover, CDP-choline increased the expression of alpha7 nicotinic acetylcholine receptor (α7 nAChR) and activated the cholinergic anti-inflammatory pathway (CAP), leading to reduced colon macrophage activation and proinflammatory M1 polarization in IBD mice, thus reducing the levels of TNF-α and IL-6. In addition, CDP-choline reduced intestinal ecological imbalance and increased the content of hexanoic acid in short-chain fatty acids (SCFAs) in mice. In conclusion, this study elucidates the ability of CDP-choline to mitigate DSS-induced colon inflammation by addressing choline and its metabolites deficiencies, activating the CAP, and regulating the composition of the intestinal microbiome and SCFAs content, providing a potential prophylactic and therapeutic approach for IBD.

Dose-dependent effects of rumen-protected choline on hepatic metabolism during induction of fatty liver in dry pregnant dairy cows.

Objectives were to determine the effects of supplementing increasing amounts of choline ion on hepatic composition and mRNA abundance in pregnant dry cows subjected to a fatty liver induction protocol. Holstein cows (35 primiparous and 41 multiparous) at mean (± standard deviation) of 211 ± 9.9 days of gestation were blocked by body condition (3.59 ± 0.33) and assigned to receive 0, 6.45, 12.90, 19.35, and 25.80 g/day of choline ion as rumen-protected choline (RPC) as a top-dress for 14 days. Cows were fed for ad libitum intake on days 1 to 5 and restricted to 30% of the required net energy for lactation from days 6 to 14 of the experiment. Hepatic tissue was sampled on days 5 and 14 and analyzed for concentrations of triacylglycerol and glycogen, and mRNA abundance was investigated. Orthogonal contrasts evaluated the effects of supplementing RPC (0 g/day vs. rest), and the linear, quadratic, and cubic effects of increasing intake of choline ion from 6.45 to 25.80 g/day. Results are depicted in sequence of treatments from 0 to 25.8. During feed restriction, RPC reduced the concentration of hepatic triacylglycerol by 28.5% and increased that of glycogen by 26.1%, and the effect of increasing RPC intake on triacylglycerol was linear (6.67 vs. 5.45 vs. 4.68 vs. 5.13 vs. 3.81 ± 0.92% wet-basis). Feeding RPC during feed restriction increased abundance of transcripts involved in choline metabolism (CHKA, PLD1), synthesis of apolipoprotein-B100 (APOB100), and antioxidant activity (GPX3), and decreased the abundance of transcripts involved in hepatic lipogenesis (DGAT2, SREBF1) and acute phase response (SAA3). Most effects were linear with amount of choline fed. Changes in hepatic mRNA abundance followed a pattern of reduced lipogenesis and enhanced lipids export, which help explain the reduced hepatic triacylglycerol content in cows fed RPC. Choline exerts lipotropic effects in dairy cows by altering transcript pathways linked to hepatic lipids metabolism.

Efficacy and mechanism of Xuefu Zhuyu Decoction on model rats of coronary heart disease with heart blood stasis syndrome based on metabolomics

This study investigated the effects of Xuefu Zhuyu Decoction on myocardial metabolites in a rat model of coronary heart disease with heart blood stasis syndrome and explored the therapeutic mechanism of blood circulation-promoting and blood stasis-removing therapy. SD rats were randomly divided into a sham operation group, a model group, a Xuefu Zhuyu Decoction group(14.04 g·kg~(-1)), and a trimetazidine group(5.4 mg·kg~(-1)). The sham operation group underwent thread insertion without ligation, while the other groups underwent coronary artery left anterior descending branch ligation to induce a model of coronary heart disease with heart blood stasis syndrome. Three days after modeling, drug intervention was performed, and samples were taken after 14 days of intervention. General conditions were observed, and electrocardiogram and cardiac ultrasound indices were measured. Hematoxylin-eosin(HE) staining and Masson staining were used to observe tissue pathological morphology. The enzyme linked immunosorbent assay(ELISA) was used to measure the levels of triglyceride(TG) and total cholesterol(TC) in the serum. Ultra high performance liquid chromatography-quantitative exactive-mass spectrometry(UHPLC-QE-MS) technology was used to screen differential metabolites in myocardial tissue and conduct metabolic pathway enrichment analysis. The results showed that Xuefu Zhuyu Decoction significantly improved the general condition of the model rats, reduced heart rate and ST segment elevation in the electrocardiogram, increased left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), and decreased left ventricular internal diameter in diastole(LVIDd) and left ventricular internal diameter in systole(LVIDs). HE staining and Masson staining showed that Xuefu Zhuyu Decoction effectively alleviated myocardial tissue structural disorders, inflammatory cell infiltration, and collagen fiber deposition in the model rats. ELISA results showed that Xuefu Zhuyu Decoction effectively regulated serum TG and TC levels in the model rats. There were significant differences in the metabolic phenotypes of myocardial samples in each group. Fourteen differential metabolites were identified in the Xuefu Zhuyu Decoction group, involving five metabolic pathways, including arginine and proline metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, ether lipid metabolism, and alanine, aspartate, and glutamate metabolism. Xuefu Zhuyu Decoction improved cardiac function and myocardial structural damage in the rat model of coronary heart disease with heart blood stasis syndrome, and its biological mechanism involved the regulation of lipid metabolism, choline metabolism, amino acid metabolism, energy metabolism, and protein synthesis pathways.

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Transcriptome and Metabolome Analyses Reveal the Mechanism of Corpus Luteum Cyst Formation in Pigs.

Corpus luteum cysts are a serious reproductive disorder that affects the reproductive performance of sows. In this study, transcriptome and metabolome datasets of porcine normal and cyst luteal granulosa cells were generated to explore the molecular mechanism of luteal cyst formation. We obtained 28.9 Gb of high-quality transcriptome data from luteum tissue samples and identified 1048 significantly differentially expressed genes between the cyst and normal corpus luteum samples. Most of the differentially expressed genes were involved in cancer and immune signaling pathways. Furthermore, 22,622 information-containing positive and negative ions were obtained through gas chromatography-mass spectrometry, and 1106 metabolites were successfully annotated. Important differentially abundant metabolites and pathways were identified, among which abnormal lipid and choline metabolism were involved in the formation of luteal cysts. The relationships between granulosa cells of luteal cysts and cancer, immune-related signaling pathways, and abnormalities of lipid and choline metabolism were elaborated, providing new entry points for studying the pathogenesis of porcine luteal cysts.

Interaction between Rumen Epithelial miRNAs-Microbiota-Metabolites in Response to Cold-Season Nutritional Stress in Tibetan Sheep.

Tibetan sheep are already well adapted to cold season nutrient stress on the Tibetan Plateau. Rumen, an important nutrient for metabolism and as an absorption organ in ruminants, plays a vital role in the cold stress adaptations of Tibetan sheep. Ruminal microbiota also plays an indispensable role in rumen function. In this study, combined multiomics data were utilized to comprehensively analyze the interaction mechanism between rumen epithelial miRNAs and microbiota and their metabolites in Tibetan sheep under nutrient stress in the cold season. A total of 949 miRNAs were identified in the rumen epithelium of both cold and warm seasons. A total of 62 differentially expressed (DE) miRNAs were screened using FC > 1.5 and p value < 0.01, and a total of 20,206 targeted genes were predicted by DE miRNAs. KEGG enrichment analysis revealed that DE miRNA-targeted genes were mainly enriched in axon guidance(ko04360), tight junction(ko04530), inflammatory mediator regulation of TRP channels(ko04750) and metabolism-related pathways. Correlation analysis revealed that rumen microbiota, rumen VFAs and DE miRNAs were all correlated. Further study revealed that the targeted genes of cold and warm season rumen epithelial DE miRNAs were coenriched with differential metabolites of microbiota in glycerophospholipid metabolism (ko00564), apoptosis (ko04210), inflammatory mediator regulation of TRP channels (ko04750), small cell lung cancer (ko05222), and choline metabolism in cancer (ko05231) pathways. There are several interactions between Tibetan sheep rumen epithelial miRNAs, rumen microbiota, and microbial metabolites, mainly through maintaining rumen epithelial barrier function and host homeostasis of choline and cholesterol, improving host immunity, and promoting energy metabolism pathways, thus enabling Tibetan sheep to effectively respond to cold season nutrient stress. The results also suggest that rumen microbiota have coevolved with their hosts to improve the adaptive capacity of Tibetan sheep to cold season nutrient stress, providing a new perspective for the study of cold season nutritional stress adaptation in Tibetan sheep.