LipidALL Technologies (China)

Apolipoprotein M (ApoM), a protein component of lipoproteins, is closely related to the development of atherosclerosis, but the specific mechanism remains elusive. Mitochondrial DNA damage can contribute to atherosclerosis, so this study was designed to investigate whether ApoM influences the structure and function of mitochondria during the progression of atherosclerosis and to explore the underlying mechanism. Atherosclerosis models were established in male ApoM-deficient (ApoM-/- ) and wild-type (ApoM+/+ ) C57BL/6 mice fed a high-fat diet (HFD), and the development of atherosclerosis was verified by en face analysis of the aorta and Masson's trichrome staining. We utilized transmission electron microscopy (TEM) to examine the ultrastructure of the aorta, its endothelial cells and EA.hy926 cells. Mass spectrometry-based lipidomics was performed to measure lipidomes in the serum and liver tissue of ApoM- /- mice. In EA.hy926 cells, we modulated the levels of autophagy and ApoM expression, and investigated the mechanism by which ApoM influences the pathogenesis of atherosclerosis through western blotting, JC-1 staining, flow cytometry, and Seahorse extracellular flux analysis. In ApoM-/- mice fed an HFD, atherosclerotic markers such as aortic lipid accumulation, fibrosis, endothelial cell oedema, and mitochondrial swelling were observed, indicating early atherosclerotic development. Lipidomic analysis revealed that ApoM deficiency might lead to impaired autophagy and mitochondrial dysfunction. In EA.hy926 cells, overexpression of ApoM not only activated autophagy but also improved mitochondrial structure. Moreover, ApoM decreased the mitochondrial membrane potential (ΔΨm) of EA.hy926 cells, which was further reduced by autophagy activation. Additionally, overexpression of ApoM in EA.hy926 cells, which have a low basal metabolism and primarily rely on glycolysis for energy, significantly reduced basal mitochondrial respiration and adenosine triphosphate (ATP) production, suggesting that ApoM can facilitate mitochondrial fission. ApoM exerts atheroprotective effects by promoting autophagy and regulating mitochondrial dynamics, thereby maintaining mitochondrial integrity and function. This study provides novel insights into the mechanisms underlying the protective role of ApoM in atherosclerosis and highlights its potential as a therapeutic target for cardiovascular diseases.

Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

BackgroundIntrinsic capacity is the combination of individual physical and mental abilities, reflecting the aging degree of the older adults. However, the mechanisms and metabolic characteristics of the decline in intrinsic capacity are still unclear.AimsTo identify metabolic signatures and associated pathways of decline in intrinsic capacity based on the metabolite features.MethodsWe recruited 70 participants aged 77.19 ± 8.31 years. The five domains of intrinsic capacity were assessed by Short Physical Performance Battery (for mobility), Montreal cognition assessment (for cognition), 30-Item Geriatric Depression Scale (for psychology), self-reported hearing/visual impairment (for sensory) and Nutritional risk screening (for vitality), respectively. The serum samples of participants were analyzed by liquid chromatography-mass spectrometry-based metabolomics, followed by metabolite set enrichment analysis and metabolic pathway analysis.ResultsThere were 50 participants with a decline in intrinsic capacity in at least one of the domains. A total of 349 metabolites were identified from their serum samples. Overall, 24 differential metabolites, 5 metabolite sets and 13 pathways were associated with the decline in intrinsic capacity.DiscussionOur results indicated that decline in intrinsic capacity had unique metabolomic profiles.ConclusionThe specific change of acyl carnitines was observed to be a feature of decline in intrinsic capacity. Dysregulation of the pentose phosphate pathway and of arginine and ornithine metabolism was strongly associated with the decline in intrinsic capacity.

Calorie restriction (CR) is a dietary intervention to promote health and longevity. CR causes various metabolic changes in both the production and circulation of metabolites; however, it remains unclear which of the changed metabolite(s) can account for the physiological benefits of CR. Through metabolomic analysis of metabolites undergoing abundance changes during CR and subsequent functional validation, we found that lithocholic acid (LCA) is the only metabolite that alone can recapitulate the effects of CR, including activation of AMPK and the rejuvenating effects of muscle regeneration, grip strength and running capacity in mice. Interestingly, LCA also activates AMPK and exerts life- and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster, indicating that these animal models are able to transmit the signalling of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes, in nematodes and flies, as well as in mice. Together, we have identified that administration of the CR-upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans, in an AMPK-dependent manner.

MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of Myod in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male Myod KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.

OsTST1 affects yield and development and mediates sugar transportation of plants from source to sink in rice, which influences the accumulation of intermediate metabolites from tricarboxylic acid cycle indirectly. Tonoplast sugar transporters (TSTs) are essential for vacuolar sugar accumulation in plants. Carbohydrate transport across tonoplasts maintains the metabolic balance in plant cells, and carbohydrate distribution is crucial to plant growth and productivity. Large plant vacuoles store high concentrations of sugars to meet plant requirements for energy and other biological processes. The abundance of sugar transporter affects crop biomass and reproductive growth. However, it remains unclear whether the rice (Oryza sativa L.) sugar transport protein OsTST1 affects yield and development. In this study, we found that OsTST1 knockout mutants generated via CRISPR/Cas9 exhibited slower development, smaller seeds, and lower yield than wild type (WT) rice plants. Notably, plants overexpressing OsTST1 showed the opposite effects. Changes in rice leaves at 14 days after germination (DAG) and at 10 days after flowering (DAF) suggested that OsTST1 affected the accumulation of intermediate metabolites from the glycolytic pathway and the tricarboxylic acid (TCA) cycle. The modification of the sugar transport between cytosol and vacuole mediated by OsTST1 induces deregulation of several genes including transcription factors (TFs). In summary, no matter the location of sucrose and sink is, these preliminary results revealed that OsTST1 was important for sugar transport from source to sink tissues, thus affecting plant growth and development.

Dairy goats experience metabolic stress during the peripartal period, and their ability to navigate this stage of lactation is related to the occurrence and development of metabolic diseases. Unlike dairy cows, there is a lack of comprehensive analysis of changes in the plasma profiles of peripartal dairy goats, particularly using high-throughput techniques. A subset of 9 clinically-healthy dairy goats were used from a cohort of 96 primiparous Guanzhong dairy goats (BCS, 2.75 ± 0.15). Blood samples were collected at seven time points around parturition (d 21, 14, 7 before parturition, the day of kidding, and d 7, 14, 21 postpartum), were analyzed using untargeted metabolomics and targeted lipidomics. The orthogonal partial least squares discriminant analysis model revealed a total of 31 differential metabolites including p-cresol sulfate, pyruvic acid, cholic acid, and oxoglutaric acid. The pathway enrichment analysis identified phenylalanine metabolism, aminoacyl-tRNA biosynthesis, and citrate cycle as the top three significantly-altered pathways. The Limma package identified a total of 123 differentially expressed lipids. Phosphatidylserine (PS), free fatty acids (FFA), and acylcarnitines (ACs) were significantly increased on the day of kidding, while diacylglycerols (DAG) and triacylglycerols (TAG) decreased. Ceramides (Cer) and lyso-phosphatidylinositols (LPI) were significantly increased during postpartum period, while PS, FFA, and ACs decreased postpartum and gradually returned to antepartum levels. Individual species of FFA and phosphatidylcholines (PC) were segregated based on the differences in the saturation and length of the carbon chain. Overall, this work generated the largest repository of the plasma lipidome and metabolome in dairy goats across the peripartal period, which contributed to our understanding of the multifaceted adaptations of transition dairy goats.