Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献_第4页

Eicosanoid biosynthesizing enzymes in Prototheria 原肠动物中的二十烷生物合成酶。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-10-09 DOI: 10.1016/j.bbalip.2024.159569

Kumar R. Kakularam , Eda Gündem , Sabine Stehling , Michael Rothe , Dagmar Heydeck , Hartmut Kuhn

Eicosanoids and related compounds are pleiotropic lipid mediators, which play a role in cell differentiation and in the pathogenesis of various diseases. The biosynthesis of these lipids has extensively been studied in highly developed mammals including humans but little is known about the formation of these mediators in more ancient Prototheria.

We searched the genomes of two extant prototherian species (platypus, short-beaked echidna) for genes encoding for lipoxygenase- (ALOX) and prostaglandin synthase-isoforms (PTGS) and detected intact single copy genes for ALOX5, ALOX12, ALOX12B, ALOXE3, PTGS1 and PTGS2. Moreover, we identified two copies of ALOX15B genes (ALOX15B-1 and ALOX15B-2) but in echidna the ALOX15B-2 gene was structurally corrupted. Interestingly, in the two genomes ALOX15 genes were lacking. For functional characterization we expressed the prototherian ALOX15B isoforms and compared important enzyme characteristics of the wildtype proteins and of relevant enzyme mutants with those of human and mouse ALOX15B. Here we observed that the prototherian ALOX15B isoforms exhibit the same reaction specificity as their human ortholog. Mutagenesis of the Triad determinants did not alter the reaction specificity of the prototherian enzymes but modification of the Jisaka determinants murinized the catalytic properties.

These data indicate that Prototheria exhibit an active eicosanoid metabolism. They express functional ALOX15B orthologs but lack ALOX15 genes. These observations and the previous findings that ALOX15 orthologs rarely occur in non-mammalian vertebrates such as fish and birds suggest that ALOX15 orthologs were introduced during Prototheria–Metatheria transition via an ALOX15B gene duplication and subsequent divergent enzyme evolution.

二十烷类脂和相关化合物是多种脂质介质，在细胞分化和各种疾病的发病机制中发挥作用。这些脂质的生物合成在包括人类在内的高度发达的哺乳动物中得到了广泛的研究，但对这些介质在更古老的原热动物中的形成却知之甚少。我们在两个现生原生动物（鸭嘴兽和短喙针鼹）的基因组中搜索了编码脂氧合酶和前列腺素合成酶同工酶的基因，发现了完整的单拷贝 ALOX5、ALOX12、ALOX12B、ALOXE3、PTGS1 和 PTGS2 基因。此外，我们还发现了两个 ALOX15B 基因拷贝（ALOX15B-1 和 ALOX15B-2），但在针鼹鼠中，ALOX15B-2 基因的结构已被破坏。有趣的是，这两个基因组中都缺少 ALOX15 基因。为了确定功能特征，我们表达了原热虫的 ALOX15B 异构体，并将野生型蛋白和相关酶突变体的重要酶特征与人类和小鼠 ALOX15B 的酶特征进行了比较。在这里，我们观察到原生动物的 ALOX15B 异构体表现出与人类同源物相同的反应特异性。对三联决定簇的突变并没有改变原生动物酶的反应特异性，但对日坂决定簇的修饰却使其催化特性变弱。这些数据表明，原肠动物表现出活跃的类二十碳烷烃代谢。它们表达功能性 ALOX15B 同源物，但缺乏 ALOX15 基因。这些观察结果以及之前发现的 ALOX15 同源物很少出现在鱼类和鸟类等非哺乳类脊椎动物中的结论表明，ALOX15 同源物是在原生动物-气象动物转变过程中通过 ALOX15B 基因复制和随后的酶进化分化引入的。

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引用次数: 0

Lipid imaging mass spectrometry: Towards a new molecular histology 脂质成像质谱：迈向新的分子组织学。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-10-05 DOI: 10.1016/j.bbalip.2024.159568

Ibai Calvo , Olatz Fresnedo , Lorena Mosteiro , José I. López , Gorka Larrinaga , José A. Fernández

Lipid research is attracting greater attention, as these molecules are key components to understand cell metabolism and the connection between genotype and phenotype. The study of lipids has also been fueled by the development of new and powerful technologies, able to identify an increasing number of species in a single run and at decreasing concentrations. One of such key developments has been the image techniques that enable the visualization of lipid distribution over a tissue with cell resolution. Thanks to the spatial information reported by such techniques, it is possible to associate a lipidome trait to individual cells, in fixed metabolic stages, which greatly facilitates understanding the metabolic changes associated to diverse pathological conditions, such as cancer. Furthermore, the image of lipids is becoming a kind of new molecular histology that has great chances to make an impact in the diagnostic units of the hospitals. Here, we examine the current state of the technology and analyze what the next steps to bring it into the diagnosis units should be. To illustrate the potential and challenges of this technology, we present a case study on clear cell renal cell carcinoma, a good model for analyzing malignant tumors due to their significant cellular and molecular heterogeneity.

脂质研究正受到越来越多的关注，因为这些分子是了解细胞新陈代谢以及基因型与表型之间联系的关键组成部分。脂质研究也得到了新的强大技术的推动，这些技术能够在一次运行中鉴定越来越多的物种，而且浓度越来越低。其中一项重要发展是图像技术，它能以细胞分辨率观察脂质在组织中的分布。得益于此类技术所报告的空间信息，可以将脂质体特征与处于固定代谢阶段的单个细胞联系起来，这大大有助于了解与癌症等各种病理情况相关的代谢变化。此外，脂质图像正在成为一种新的分子组织学，很有可能在医院诊断部门产生影响。在此，我们研究了该技术的现状，并分析了将其引入诊断部门的下一步措施。为了说明这项技术的潜力和挑战，我们介绍了一个关于透明细胞肾细胞癌的案例研究，由于其显著的细胞和分子异质性，透明细胞肾细胞癌是分析恶性肿瘤的良好模型。

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引用次数: 0

Sex-specific response of the human plasma lipidome to short-term cold exposure 人体血浆脂质体对短期寒冷暴露的反应具有性别特异性。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-10-02 DOI: 10.1016/j.bbalip.2024.159567

Marcus Höring , Sarah Brunner , Josef Scheiber , Julius Honecker , Gerhard Liebisch , Claudine Seeliger , Laura Schinhammer , Melina Claussnitzer , Ralph Burkhardt , Hans Hauner , Josef Ecker

Cold-induced lipolysis is widely studied as a potential therapeutic strategy to combat metabolic disease, but its effect on lipid homeostasis in humans remains largely unclear. Blood plasma comprises an enormous repertoire in lipids allowing insights into whole body lipid homeostasis. So far, reported results originate from studies carried out with small numbers of male participants. Here, the blood plasma's lipidome of 78 male and 93 female volunteers, who were exposed to cold below the shivering threshold for 2 h, was quantified by comprehensive lipidomics using high-resolution mass spectrometry. Short-term cold exposure increased the concentrations in 147 of 177 quantified circulating lipids and the response of the plasma's lipidome was sex-specific. In particular, the amounts of generated glycerophospholipid and sphingolipid species differed between the sexes. In women, the BMI could be related with the lipidome's response. A logistic regression model predicted with high sensitivity and specificity whether plasma samples were from male or female subjects based on the cold-induced response of phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) species.

In summary, cold exposure promotes lipid synthesis by supplying fatty acids generated after lipolysis for all lipid classes. The plasma lipidome, i.e. PC, LPC and SM, shows a sex-specific response, indicating a different regulation of its metabolism in men and women. This supports the need for sex-specific research and avoidance of sex bias in clinical trials.

冷诱导脂肪分解作为一种潜在的治疗策略被广泛研究，以防治代谢性疾病，但其对人体脂质稳态的影响在很大程度上仍不清楚。血浆中的脂质种类繁多，因此可以深入了解全身脂质的稳态。迄今为止，所报道的结果都是针对少数男性参与者进行的研究。在此，我们利用高分辨率质谱技术，通过全面的脂质组学研究，对 78 名男性志愿者和 93 名女性志愿者的血浆脂质体进行了定量分析。在 177 种被量化的循环脂质中，有 147 种的浓度在短期寒冷暴露后有所增加，血浆脂质组的反应具有性别特异性。特别是，生成的甘油磷脂和鞘脂种类的数量因性别而异。在女性中，体重指数与脂质体的反应有关。根据冷诱导的磷脂酰胆碱（PC）、溶血磷脂酰胆碱（LPC）和鞘磷脂（SM）种类的反应，逻辑回归模型能高灵敏度和特异性地预测血浆样本是来自男性还是女性。总之，冷暴露通过为所有脂质类别提供脂肪分解后产生的脂肪酸来促进脂质合成。血浆脂质体（即 PC、LPC 和 SM）显示出性别特异性反应，表明男性和女性的脂质代谢调节方式不同。这说明有必要进行性别特异性研究，并避免在临床试验中出现性别偏见。

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引用次数: 0

Dysregulation of lipid metabolism in the liver of Tspo knockout mice Tspo 基因敲除小鼠肝脏脂质代谢失调。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-09-29 DOI: 10.1016/j.bbalip.2024.159566

Fahad Farhan , Rakesh Kotapati Raghupathy , Michal R. Baran , Aileen Wong , Lincoln Biswas , Hui-Rong Jiang , John A. Craft , Xinhua Shu

The translocator protein, TSPO, has been implicated in a wide range of cellular processes exerted from its position in the outer mitochondrial membrane from where it influences lipid metabolism and mitochondrial oxidative activity. Understanding how this protein regulates a profusion of processes requires further elucidation and to that end we have examined lipid metabolism and used an RNAseq strategy to compare transcript abundance in wildtype and Tspo knockout (KO) mouse liver. The levels of cholesterol, triglyceride and phospholipid were significantly elevated in the KO mouse liver. The expression of cholesterol homeostasis genes was markedly downregulated. Determination of the differential expression revealed that many genes were either up- or downregulated in the KO animals. However, a striking observation within the results was a decrease of transcripts for protein degradation proteins in KO animals while protease inhibitors were enriched. When the entire abundance data-set was analysed with CEMiTool, and revealed a module of proteins that were under-represented in the KO animals. These could subsequently be formed into a network comprising three interlinked clusters at the centre of which were proteins of cytoplasmic ribosomes with gene ontology terms suggesting impairment to translation. The largest cluster was dominated by proteins of lipid metabolism but also contained disparate systems of iron metabolism and behaviour. The third cluster was dominated by proteins of the electron transport chain and oxidative phosphorylation. These findings suggest that TSPO contributes to lipid metabolism, detoxification of active oxygen species and oxidative phosphorylation, and regulates mitochondrial retrograde signalling.

转运蛋白 TSPO 位于线粒体外膜，影响着线粒体的脂质代谢和氧化活性，因此与多种细胞过程都有关系。要了解这种蛋白质是如何调控一系列过程的，还需要进一步阐明。为此，我们研究了脂质代谢，并使用 RNAseq 策略比较了野生型和 Tspo 基因敲除（KO）小鼠肝脏中的转录本丰度。在 KO 小鼠肝脏中，胆固醇、甘油三酯和磷脂的水平显著升高。胆固醇平衡基因的表达明显下调。差异表达的测定结果表明，许多基因在 KO 动物体内要么上调，要么下调。然而，结果中一个引人注目的现象是，KO 动物体内蛋白质降解蛋白的转录本减少了，而蛋白酶抑制剂却富集了。当使用 CEMiTool 分析整个丰度数据集时，发现了一个在 KO 动物中代表性不足的蛋白质模块。这些蛋白质随后可以组成一个由三个相互关联的簇组成的网络，簇的中心是细胞质核糖体蛋白质，其基因本体术语表明它们的翻译功能受到了损害。最大的集群以脂质代谢蛋白为主，但也包含不同的铁代谢和行为系统。第三组主要是电子传递链和氧化磷酸化的蛋白质。这些发现表明，TSPO 有助于脂质代谢、活性氧解毒和氧化磷酸化，并能调节线粒体逆行信号。

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引用次数: 0

Seasonal and genetic effects on lipid profiles of juvenile Atlantic salmon 季节和遗传对大西洋鲑幼鱼脂质特征的影响。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-09-26 DOI: 10.1016/j.bbalip.2024.159565

Andrew H. House , Paul V. Debes , Minna Holopainen , Reijo Käkelä , Iikki Donner , Morgane Frapin , Ehsan Pashay Ahi , Johanna Kurko , Hanna Ruhanen , Craig R. Primmer

Seasonality can influence many physiological traits requiring optimal energetic capacity for life-history stage transitions. In Atlantic salmon, high-energy status is essential for the initiation of maturation. Earlier studies have linked a genomic region encoding vgll3 to maturation age, potentially mediated via body condition. Vgll3 has also been shown to act as an inhibitor of adipogenesis in mice. Here we investigate the influence of season and vgll3 genotypes associating with early (EE) and late (LL) maturation on lipid profiles in the muscle and liver of juvenile Atlantic salmon. We reared Atlantic salmon for two years from fertilization and sampled muscle and liver during the spring and autumn of the second year (at which time some males were sexually mature). We found no seasonal or genotype effect in the muscle lipid profiles of immature males or females. However, in the liver we detected a triacylglycerol enrichment and a genotype specific direction of change in membrane lipids, phosphatidylcholine and phosphatidylethanolamine, from spring to autumn. Specifically, from spring to autumn membrane lipid concentrations increased in vgll3*EE individuals but decreased in vgll3*LL individuals. This could be explained by 1) a seasonally more stable capacity of endoplasmic reticulum (ER) functions in vgll3*EE individuals compared to vgll3*LL individuals or 2) vgll3*LL individuals storing larger lipid droplets from spring to autumn in the liver compared to vgll3*EE individuals at the expense of ER capacity. This genotype specific seasonal direction of change in membrane lipid concentrations provides more indirect evidence of a potential mechanism linking vgll3 with lipid metabolism and storage.

季节性会影响许多生理特征，这些特征需要最佳的能量能力来完成生命阶段的转换。在大西洋鲑鱼中，高能量状态对于启动成熟至关重要。早期的研究已将编码 vgll3 的基因组区域与成熟年龄联系起来，这可能是通过身体状况介导的。Vgll3 还被证明是小鼠脂肪生成的抑制剂。在此，我们研究了与早熟（EE）和晚熟（LL）相关的季节和 vgll3 基因型对大西洋鲑幼鱼肌肉和肝脏脂质特征的影响。我们从大西洋鲑受精开始饲养了两年，并在第二年的春季和秋季对其肌肉和肝脏取样（此时部分雄性大西洋鲑已性成熟）。我们发现，未成熟雄性和雌性鲑鱼的肌肉脂质特征没有季节或基因型的影响。然而，在肝脏中，我们检测到三酰甘油富集以及膜脂质、磷脂酰胆碱和磷脂酰乙醇胺从春季到秋季的特定基因型变化方向。具体来说，从春季到秋季，vgll3*EE个体的膜脂浓度增加，而vgll3*LL个体的膜脂浓度降低。这可能是由于：1）与 vgll3*LL 基因型个体相比，vgll3*EE 基因型个体的内质网（ER）功能在季节性上更加稳定；或 2）与 vgll3*EE 基因型个体相比，vgll3*LL 基因型个体从春到秋在肝脏中储存的脂滴更大，但却牺牲了ER的能力。膜脂浓度的这种基因型特异性季节变化方向为 vgll3 与脂质代谢和储存的潜在联系机制提供了更多间接证据。

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引用次数: 0

Re-evaluation of the canonical PAF pathway in cutaneous anaphylaxis 重新评估皮肤过敏性休克的典型 PAF 通路。

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-09-25 DOI: 10.1016/j.bbalip.2024.159563

Tomoyuki Suzuki , Yoshitaka Taketomi , Keisuke Yanagida , Tomomi Yoshida-Hashidate , Takahide Nagase , Makoto Murakami , Takao Shimizu , Hideo Shindou

Platelet-activating factor (PAF) is a potent classical lipid mediator that plays a critical role in various diseases such as allergy and nervous system disorders. In the realm of allergy, previous studies suggested that PAF is generated in response to extracellular stimuli and contributes to allergic reactions via PAF receptor (PAFR). However, the sources of endogenous PAF and its pathophysiological dynamics remain largely elusive in vivo. Here, we report that rapid and local PAF generation completely depends on lysophospholipid acyltransferase 9 (LPLAT9, also known as LPCAT2) expressed in mast cells in IgE-mediated passive cutaneous anaphylaxis. However, we found that LPLAT9 knockout (KO) mice did not display attenuated vascular leakage. Additionally, decreased vascular leakage was observed in PAFR KO mice, but not in endothelial cell-specific mice in this model. These divergences highlight a yet unsolved complexity of the biological functions of PAF and PAFR in a pathophysiological process.

血小板活化因子（PAF）是一种强效的经典脂质介质，在过敏和神经系统疾病等多种疾病中发挥着至关重要的作用。在过敏领域，先前的研究表明 PAF 是在对细胞外刺激做出反应时产生的，并通过 PAF 受体（PAFR）促成过敏反应。然而，内源性 PAF 的来源及其在体内的病理生理动态在很大程度上仍然难以捉摸。在这里，我们报告了在 IgE 介导的被动皮肤过敏性休克中，局部 PAF 的快速生成完全依赖于肥大细胞中表达的溶血磷脂酰基转移酶 9（LPLAT9，又称 LPCAT2）。然而，我们发现 LPLAT9 基因敲除（KO）小鼠的血管渗漏并没有减少。此外，在该模型中，PAFR KO 小鼠的血管渗漏减少，而内皮细胞特异性小鼠则没有。这些分歧凸显了 PAF 和 PAFR 在病理生理过程中的生物功能的复杂性，而这一复杂性尚未得到解决。

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引用次数: 0

Recent advances on the physiological and pathophysiological roles of polyunsaturated fatty acids and their biosynthetic pathway 多不饱和脂肪酸的生理和病理作用及其生物合成途径的最新进展

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-09-24 DOI: 10.1016/j.bbalip.2024.159564

Hyeon-Cheol Lee-Okada, Chengxuan Xue, Takehiko Yokomizo

Polyunsaturated fatty acids (PUFAs)—fatty acids containing multiple double bonds within their carbon chain—are an indispensable component of the cell membrane. PUFAs, including the omega-6 PUFA arachidonic acid (ARA; C20:4n-6) and the omega-3 PUFAs eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), have been implicated in various (patho)physiological events. These PUFAs are either obtained from the diet or biosynthesized from the essential fatty acids linoleic acid (LA; C18:2n-6) and α-linolenic acid (ALA; C18:3n-3) via enzymatic reactions that are catalyzed by fatty acid elongases (ELOVL2 and ELOVL5) and fatty acid desaturases (FADS1 and FADS2). In this review, we summarize the recent literature studying the role of PUFAs, placing a special emphasis on the newly discovered functions of PUFAs and their biosynthetic pathway as revealed by studies using animal models targeting the PUFA biosynthetic pathway and genetic approaches including genome-wide association studies.

多不饱和脂肪酸（PUFA）--碳链中含有多个双键的脂肪酸--是细胞膜不可或缺的组成部分。多不饱和脂肪酸，包括ω-6 多不饱和脂肪酸花生四烯酸（ARA；C20:4n-6）和ω-3 多不饱和脂肪酸二十碳五烯酸（EPA；C20:5n-3）和二十二碳六烯酸（DHA；C22:6n-3），与各种（病理）生理事件有关。这些 PUFA 或从膳食中获取，或由必需脂肪酸亚油酸（LA；C18:2n-6）和α-亚麻酸（ALA；C18:3n-3）通过脂肪酸延长酶（ELOVL2 和 ELOVL5）和脂肪酸去饱和酶（FADS1 和 FADS2）催化的酶促反应生物合成。在这篇综述中，我们总结了近期研究 PUFA 作用的文献，并特别强调了通过针对 PUFA 生物合成途径的动物模型研究和包括全基因组关联研究在内的遗传方法所揭示的 PUFA 及其生物合成途径的新功能。

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引用次数: 0

Lipidomic and transcriptomic characteristics of boar seminal plasma extracellular vesicles associated with sperm motility 与精子活力相关的公猪精浆细胞外囊泡的脂质组和转录组特征

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-09-02 DOI: 10.1016/j.bbalip.2024.159561

Ning Ding, Yu Zhang, Jiayao Wang, Jianfeng Liu, Jing Zhang, Chun Zhang, Lei Zhou, Jinkang Cao, Li Jiang

Seminal plasma extracellular vesicles (SPEVs) play an important role in regulating sperm motility by delivering various cargoes, such as miRNAs, mRNAs, proteins and metabolites. However, information on the lipid compositions of SPEVs and their roles in semen quality is limited. Here, we performed high-throughput transcriptomic and lipidomic analysis on SPEVs isolated from 20 boars with high or low sperm motility. Then, we evaluated the lipid composition and gene expression characteristics of SPEVs and identified the specific lipids and genes related to sperm motility. As a result, a total of 26 lipid classes were identified in SPEVs, and five subclasses, CerG2, CerG3, LPE, LPS and TG, were significantly different in boars with high and low sperm motility. In addition, 195 important lipids and 334 important genes were identified by weighted gene coexpression analysis (WGCNA) and differential expression analysis. We observed that several important genes and lipids in SPEVs potentially influence sperm motility via glycerophospholipid metabolism, glycerolipid metabolism, the sphingolipid signaling pathway and the ferroptosis pathway. Furthermore, we found a significant correlation between the content of 22 lipids and the expression levels of 67 genes (|cor| > 0.8, P < 0.05). Moreover, we observed that three important gene-lipid linkages (CerG1 (d22:0/24:0) - RCAN3, Cer (d18:1/24:0) - SCFD2 and CerG1 (d18:0/24:1) - SCFD2) were strongly correlated with sperm motility. Based on the results, some genes and lipids in SPEVs may play important roles in sperm motility by interacting with sperm through important pathways.

精浆细胞外囊泡（SPEVs）通过运送各种货物，如 miRNAs、mRNAs、蛋白质和代谢物，在调节精子活力方面发挥着重要作用。然而，有关 SPEVs 的脂质成分及其在精液质量中的作用的信息却很有限。在这里，我们对从20头精子活力高或低的公猪体内分离出的SPEV进行了高通量转录组和脂质组分析。然后，我们评估了 SPEVs 的脂质组成和基因表达特征，并确定了与精子活力相关的特定脂质和基因。结果发现，SPEVs中共有26类脂质，其中CerG2、CerG3、LPE、LPS和TG这5个亚类在精子活力高的公猪和精子活力低的公猪中存在显著差异。此外，通过加权基因共表达分析（WGCNA）和差异表达分析，确定了 195 种重要脂质和 334 个重要基因。我们观察到，SPEVs中的几个重要基因和脂质可能会通过甘油磷脂代谢、甘油脂质代谢、鞘脂信号通路和铁突变通路影响精子活力。此外，我们还发现 22 种脂类的含量与 67 个基因的表达水平之间存在明显的相关性（|cor| > 0.8, P <0.05）。此外，我们还观察到三个重要的基因-脂质联系（CerG1 (d22:0/24:0) - RCAN3、Cer (d18:1/24:0) - SCFD2 和 CerG1 (d18:0/24:1) - SCFD2）与精子活力密切相关。根据这些结果，SPEVs 中的一些基因和脂质可能通过重要途径与精子相互作用，从而在精子活力中发挥重要作用。

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引用次数: 0

Cold-induced phosphatidylethanolamine synthesis in liver and brown adipose tissue of mice 冷诱导小鼠肝脏和棕色脂肪组织中磷脂酰乙醇胺的合成

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-08-28 DOI: 10.1016/j.bbalip.2024.159562

Maria Soledad Hidrobo , Marcus Höring , Sarah Brunner , Gerhard Liebisch , Sabine Schweizer , Martin Klingenspor , Renate Schreiber , Rudolf Zechner , Ralph Burkhardt , Josef Ecker

Increasing energy expenditure in brown adipose (BAT) tissue by cold-induced lipolysis is discussed as a potential strategy to counteract imbalanced lipid homeostasis caused through unhealthy lifestyle and cardiometabolic disease. Yet, it is largely unclear how liberated fatty acids (FA) are metabolized. We investigated the liver and BAT lipidome of mice housed for 1 week at thermoneutrality, 23 °C and 4 °C using quantitative mass spectrometry-based lipidomics. Housing at temperatures below thermoneutrality triggered the generation of phosphatidylethanolamine (PE) in both tissues. Particularly, the concentrations of PE containing polyunsaturated fatty acids (PUFA) in their acyl chains like PE 18:0_20:4 were increased at cold. Investigation of the plasma's FA profile using gas chromatography coupled to mass spectrometry revealed a negative correlation of PUFA with unsaturated PE in liver and BAT indicating a flux of FA from the circulation into these tissues. Beta-adrenergic stimulation elevated intracellular levels of PE 38:4 and PE 40:6 in beige wildtype adipocytes, but not in adipose triglyceride lipase (ATGL)-deficient cells. These results imply an induction of PE synthesis in liver, BAT and thermogenic adipocytes after activation of the beta-adrenergic signaling cascade.

通过冷诱导脂肪分解来增加棕色脂肪组织（BAT）的能量消耗被认为是一种潜在的策略，可用于对抗不健康的生活方式和心脏代谢疾病导致的脂质平衡失调。然而，目前还不清楚释放的脂肪酸（FA）是如何代谢的。我们利用基于质谱的定量脂质组学研究了在恒温、23 °C和4 °C条件下饲养1周的小鼠的肝脏和BAT脂质体。在低于恒温的温度下饲养会引发两种组织中磷脂酰乙醇胺（PE）的生成。尤其是在低温条件下，磷脂酰链中含有多不饱和脂肪酸（PUFA）（如 PE 18:0_20:4）的磷脂酰乙醇胺的浓度增加。利用气相色谱-质谱联用技术对血浆中的不饱和脂肪酸概况进行的调查显示，肝脏和 BAT 中的多不饱和脂肪酸与不饱和 PE 呈负相关，这表明不饱和脂肪酸从血液循环进入了这些组织。β-肾上腺素能刺激会提高米色野生型脂肪细胞中 PE 38:4 和 PE 40:6 的细胞内水平，但不会提高脂肪甘油三酯脂酶（ATGL）缺陷细胞中的水平。这些结果表明，β-肾上腺素能信号级联激活后，会诱导肝脏、BAT 和生热脂肪细胞中的 PE 合成。

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引用次数: 0

Spermidine mitigates ferroptosis in free fatty acid-induced AML-12 cells through the ATF4/SLC7A11/GCLM/GPX4 pathway 精胺通过 ATF4/SLC7A11/GCLM/GPX4 通路减轻游离脂肪酸诱导的 AML-12 细胞的铁变态反应

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids

Pub Date : 2024-08-22 DOI: 10.1016/j.bbalip.2024.159560

Jia Zhang, Tao Zhang, Yihang Chen, Xiaojie Xuan, Yuqian Zhao, Gaofeng Lu

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease worldwide. Spermidine (SPD), a naturally occurring polyamine, has shown potential in alleviating the accumulation of hepatic lipids and reducing NAFLD symptoms in overweight mice. Nonetheless, the specific mechanisms through which SPD exerts its effects remain largely unknown. This study seeks to explore the protective effects of SPD on NAFLD and to clarify the underlying mechanisms. An in vitro model of NAFLD was established by inducing steatosis in AML-12 cells through the use of free fatty acids (FFAs). Our experimental results demonstrate that SPD significantly reduces NAFLD development induced by FFAs. This reduction is primarily achieved through the inhibition of cellular ferroptosis, as evidenced by decreased levels of Fe²⁺, malondialdehyde (MDA), and reactive oxygen species (ROS). Additionally, SPD was found to enhance cellular activity and ameliorate mitochondrial dysfunction and oxidative stress caused by FFA exposure.

Further mechanistic studies have revealed that SPD upregulates the expression of solute transporter family 7a member 11 (SLC7A11), glutamate-cysteine ligase modifier subunit (GCLM), and glutathione peroxidase (GPX4). This upregulation is mediated by the activation of activating transcription factor 4 (ATF4). Knockdown experiments of ATF4 confirmed that its inhibition reverses the upregulation of SLC7A11, GCLM, and GPX4, thereby negating the protective effects of SPD. In conclusion, our findings suggest that SPD mitigates NAFLD by modulating the ATF4/SLC7A11/GCLM/GPX4 signaling pathway, resulting in the suppression of ferroptosis and the improvement of cellular health. These insights provide a novel molecular mechanism and identify potential therapeutic targets for the treatment of NAFLD.

非酒精性脂肪肝（NAFLD）是全球慢性肝病的主要病因。精胺（SPD）是一种天然多胺，在减轻超重小鼠肝脏脂质积累和减轻非酒精性脂肪肝症状方面具有潜力。然而，SPD 发挥作用的具体机制在很大程度上仍不为人所知。本研究旨在探索 SPD 对非酒精性脂肪肝的保护作用，并阐明其潜在机制。通过使用游离脂肪酸（FFAs）诱导 AML-12 细胞发生脂肪变性，建立了非酒精性脂肪肝的体外模型。我们的实验结果表明，SPD 能显著降低游离脂肪酸诱导的非酒精性脂肪肝的发展。这种降低主要是通过抑制细胞铁变态反应来实现的，Fe2+、丙二醛（MDA）和活性氧（ROS）水平的降低就是证明。进一步的机理研究发现，SPD 能上调溶质转运体家族 7a 成员 11（SLC7A11）、谷氨酸-半胱氨酸连接酶修饰亚基（GCLM）和谷胱甘肽过氧化物酶（GPX4）的表达。这种上调是通过激活转录因子 4（ATF4）介导的。敲除 ATF4 的实验证实，抑制 ATF4 可逆转 SLC7A11、GCLM 和 GPX4 的上调，从而抵消 SPD 的保护作用。总之，我们的研究结果表明，SPD可通过调节ATF4/SLC7A11/GCLM/GPX4信号通路缓解非酒精性脂肪肝，从而抑制铁变态反应并改善细胞健康。这些见解提供了一种新的分子机制，并为治疗非酒精性脂肪肝确定了潜在的治疗靶点。

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引用次数: 0