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Altered levels of sphingomyelins, ceramides, glycerophospholipids, and diacylglycerols in thymoma tissues 胸腺瘤组织中鞘磷脂、神经酰胺、甘油磷脂和二酰基甘油水平的改变
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-18 DOI: 10.1016/j.bbalip.2025.159650
Jie Zhang , Xiaoling Zang , Wei Meng , Peng Jiao , Jiangyu Wu , Lizhen Zhao , Zhuangzhuang Li , Xin Zhang , Huanhuan Yang , Zhihua Lv
Thymoma is a rare thymic epithelial tumor, and its pathogenesis and lipid characteristics are still unclear. In this study, non-targeted lipidomics study by ultra-performance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS) was conducted to analyze the alterations of lipids in 76 tissue samples from 24 thymoma, 14 thymic hyperplasia, and 1 thymic carcinoma (TC) patients. Sphingomyelins with 36–44 carbons (SM d36:1, SM d38:1, SM d40:1, SM d36:2, SM d38:2, SM d40:2, SM d41:2, SM d43:2, SM d44:2), medium, long and very-long chain ceramides (Cer d17:1/16:0, Cer d18:1/17:0, Cer d18:1/18:0, Cer d18:1/22:0, Cer d18:1/24:1, Cer d18:2/20:0, Cer d18:2/22:0), phosphatidylcholine (PC) 16:0_16:0, phosphatidylethanolamines (PE 16:0_16:0, PE 16:0_16:1, PE P-16:0_18:2), LPE 18:2, phosphatidylserine (PS) 18:1_22:0, diacylglycerols (DG 16:0_18:1 and DG 18:1_18:2) showed decreased levels, while polyunsaturated lysophosphatidylcholines (LPCs), PCs with long or very-long polyunsaturated acyl chains (PC 16:0_18:3, PC 18:0_22:5, PC 18:1_22:6, PC 15:0_18:2, PC 18:0_20:3, PC 18:0_20:4, PC 18:2_20:4, PC 20:2_20:4, PC 18:0_22:4, PC 20:4_22:4, PC O-18:0_20:4), part of identified PEs (PE P-16:0_18:1, PE P-18:0_20:4, PE P-16:0_22:6), DG 18:0_20:4, arachidyl carnitine, and 1-methylhistamine had increased levels in thymoma and 1 TC tissues compared to paired non-cancerous tissues. The most altered pathways in thymoma tissues were glycerophospholipid metabolism and sphingolipid metabolism. In addition, orthogonal partial least squares-discriminant analysis (oPLS-DA) based on 5 lipids (PC 18:0_20:3, PE 16:0_16:0, PC 18:0_22:5, PE P-16:0_18:1, and PC O-18:0_20:4) discriminated thymoma and 1 TC tissues from non-cancerous ones with 97.4 % accuracy, 100 % sensitivity, and 95.5 % specificity, showing a good discrimination ability.
胸腺瘤是一种罕见的胸腺上皮性肿瘤,其发病机制和脂质特征尚不清楚。本研究采用超高效液相色谱-高分辨率质谱法(UPLC-HRMS)进行非靶向脂质组学研究,分析了24例胸腺瘤、14例胸腺增生和1例胸腺癌(TC)患者76份组织样本的脂质变化。含36-44碳的鞘磷脂(SM d36:1, SM d38:1, SM d40:1, SM d36:2, SM d38:2, SM d40:2, SM d41:2, SM d43:2, SM d44:2),中链、长链和超长链神经酰胺(Cer d17:1 16:0, Cer d18:1 17:0, Cer d18:1 18:0, Cer d18:1 22:0, Cer d18:1 24:1, Cer d18:2 20:0, Cer d18:2 22:0),磷脂酰胆碱(PC) 16:0 -16:0,磷脂酰乙醇胺(PE 16:0 -16:0, PE 16:0 -16:0 - 16:1, PE p -16:0 - 18:0 - 18:2), LPE 18:2,磷脂酰丝氨酸(PS) 18:1_22:0,多不饱和溶血磷脂酰胆碱(lpc)、长或超长多不饱和酰基链的溶血磷脂酰胆碱(PC 16:0_18:3、PC 18:0_22:5、PC 18:1_22:6、PC 15:0_18:2、PC 18:0_20:3、PC 18:0_20:4、PC 18:2_20:4、PC 20:2_20:4、PC 18:0_22:4、PC O-18:0_20:4)、部分已鉴定的PE (PE P-16:0_18:1、PE P-18:0_20:4、PE p -16:0 _22:4、PE P-16:0_22:6)、DG 18:0_20:4、肉碱。与配对的非癌组织相比,胸腺瘤和TC组织中的1-甲基组胺水平升高。胸腺瘤组织中变化最大的途径是甘油磷脂代谢和鞘脂代谢。此外,基于5种脂质(PC 18:0_20:3、PE 16:0_16:0、PC 18:0_22:5、PE P-16:0_18:1、PC O-18:0_20:4)的正交偏最小二乘判别分析(oPLS-DA)将胸腺瘤和1 TC组织与非癌组织区分开来,准确率为97.4%,灵敏度为100%,特异性为95.5%,具有较好的判别能力。
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引用次数: 0
Cold-sensitive pathway elongates a non-native cis-7-hexadecenoic acid to cis-9-octadecenoic acid in the cyanobacterium Synechocystis sp. PCC 6803 在藻胞杆菌PCC 6803中,冷敏感途径将非天然的顺-7-十六烯酸延长为顺-9-十八烯酸
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-16 DOI: 10.1016/j.bbalip.2025.159649
Asuka Kobayashi , Nattiwong Pankasem , Kotaro Kobayashi , Florence Corellou , Kohei Yoneda , Yoshiaki Maeda , Iwane Suzuki
Cellular membranes of the cyanobacterium Synechocystis sp. PCC 6803 primarily consist of glycerolipids esterified unsaturated C18 and saturated C16 fatty acids (FAs). We introduced the Ot17.2 gene from the Mamiellophyceae Ostreococcus tauri into Synechocystis. The cells, Ot17.2+, produced cis-7-hexadecenoic acid (hypogeic acid, 16:1∆7) at the half level of the total C16 FAs, suggesting that the Ot17.2 gene encodes chloroplast-localized C16-specific ∆7 desaturase. To study the effect of the synthesis of a non-native unsaturated C16 FA, we attempted to decrease the copy number of the desC gene for C18-specific ∆9 desaturase, producing cis-9-octadecenoic acid (oleic acid, 18:1∆9) in the Ot17.2+ strain. Surprisingly, the desC gene was entirely deleted in the Ot17.2+/desC- strain, despite the knowledge that the desC gene is essential for survival. We found that the C18 FAs in the strain were unsaturated as in the wild-type cells. In contrast, we could not delete the desC gene completely in the cells expressing the desC2 gene for the C16 specific ∆9 desaturase, producing cis-9-hexadecenoic acid (palmitoleic acid, 16:1∆9). These findings indicate that Synechocystis may synthesize 18:1∆9 from 16:1∆7 via FA elongation, and cis-11-octade cenoic acid (vaccenic acid, 18:1∆11) produced from the elongation of 16:1∆9 may not sustain the cell growth. Interestingly, this strain (Ot17.2+/desC- strain) did not grow and produced little C18 unsaturated FAs at low temperatures. The supply of either 18:1∆9 or 16:1∆7 into the culture of Ot17.2+/desC- supported the growth, suggesting that the lipase activity involved in the FA salvage and elongation system might be severely sensitive to low temperatures.
聚胞藻(synnechocystis sp. PCC 6803)的细胞膜主要由酯化的不饱和C18和饱和C16脂肪酸(FAs)组成。我们将牛链球菌的Ot17.2基因导入聚胞菌中。细胞Ot17.2+产生的顺式-7-十六烯酸(hypogeic acid, 16:1∆7)是C16 FAs总量的一半,表明Ot17.2基因编码叶绿体定位的C16特异性∆7去饱和酶。为了研究非天然不饱和C16 FA合成的影响,我们尝试降低c18特异性∆9去饱和酶desC基因的拷贝数,在Ot17.2+菌株中产生顺式-9-十八烯酸(油酸,18:1∆9)。令人惊讶的是,尽管已知desC基因对生存至关重要,但在Ot17.2+/desC-菌株中desC基因被完全删除。我们发现菌株的C18 FAs与野生型细胞一样是不饱和的。相比之下,对于C16特异性的∆9去饱和酶,我们不能在表达desC2基因的细胞中完全删除desC基因,产生顺式-9-十六烯酸(棕榈油酸,16:1∆9)。这些结果表明,聚囊藻可以通过FA伸长由16:1∆7合成18:1∆9,而由16:1∆9伸长产生的顺式-11-辛烷酸(异戊酸,18:1∆11)可能无法维持细胞生长。有趣的是,该菌株(Ot17.2+/desC-菌株)在低温下不生长,产生少量C18不饱和脂肪酸。在Ot17.2+/desC-培养液中添加18:1∆9或16:1∆7均支持生长,表明参与FA回收和延伸系统的脂肪酶活性可能对低温非常敏感。
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引用次数: 0
Adcy8 deficiency contributes to impaired lipolysis and an increased prevalence of obesity in mice Adcy8缺乏导致小鼠脂肪分解受损和肥胖患病率增加
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-16 DOI: 10.1016/j.bbalip.2025.159648
Mengxue Han , Qing Shu , Ruili Yu , Shaohong Wu , Handan Deng , Yang Liu , Quan Yu , Wei Li , Luyang Gao , Yawen Zhao , Geyang Xu
Obesity is a global chronic disease characterized by an imbalance in energy homeostasis. Dysfunction of adipocytes and adipose tissue are fundamental defects that contribute to the development of obesity. Adenylate cyclase 8 (ADCY8) serves as a key downstream signaling factor of G protein-coupled receptors, catalyzing the conversion of ATP to cyclic AMP (cAMP), which is essential for maintaining energy balance. Although ADCY8 is expressed in adipose tissue, its specific role in adipose energy homeostasis remains unclear and warrants further investigation. Our findings demonstrate that compared to individuals with a normal body mass index (BMI), obese individuals exhibit increased visceral adipose tissue (VAT) accumulation, significantly enlarged adipocytes, reduced ADCY8 expression in VAT, decreased cAMP levels, and diminished phosphorylation of key lipolytic enzymes. In Adcy8 knockout (Adcy8−/−) mice, more severe lipid accumulation was observed under both normal and high-fat diet (HFD) conditions, accompanied by reduced activity of the adipose tissue cAMP-PKA signaling pathway. Notably, forskolin enhanced lipolysis and reduced adipocyte size in diet-induced obese wild-type mice, an effect abrogated in Adcy8−/− mice. Collectively, these results indicate that adipose tissue ADCY8 regulates phosphorylation of lipolysis-related proteins via the cAMP-PKA signaling pathway, thereby influencing adipose tissue lipid accumulation. These findings establish ADCY8 as a novel molecular target and provide a theoretical foundation for obesity therapy.
肥胖是一种以能量平衡失衡为特征的全球性慢性疾病。脂肪细胞和脂肪组织的功能障碍是导致肥胖的根本缺陷。腺苷酸环化酶8 (Adenylate cyclase 8, ADCY8)是G蛋白偶联受体的关键下游信号因子,催化ATP转化为环AMP (cyclic AMP, cAMP),对维持能量平衡至关重要。虽然ADCY8在脂肪组织中表达,但其在脂肪能量稳态中的具体作用尚不清楚,值得进一步研究。我们的研究结果表明,与正常体重指数(BMI)的个体相比,肥胖个体表现出内脏脂肪组织(VAT)积累增加,脂肪细胞显著增加,VAT中ADCY8表达减少,cAMP水平降低,关键脂溶酶磷酸化减少。在Adcy8敲除(Adcy8−/−)小鼠中,在正常和高脂饮食(HFD)条件下,均观察到更严重的脂质积累,并伴有脂肪组织cAMP-PKA信号通路活性降低。值得注意的是,在饮食诱导的肥胖野生型小鼠中,forskolin增强了脂肪分解并减少了脂肪细胞大小,而在Adcy8 - / -小鼠中则没有这种作用。综上所述,这些结果表明脂肪组织ADCY8通过cAMP-PKA信号通路调节脂肪分解相关蛋白的磷酸化,从而影响脂肪组织脂质积累。这些发现确立了ADCY8作为一种新的分子靶点,为肥胖治疗提供了理论基础。
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引用次数: 0
Hyperoxic recovery impacts on metabolic adaptations induced by hypoxic exercise: A lipidomics approach 高氧恢复对低氧运动诱导的代谢适应的影响:脂质组学方法
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-14 DOI: 10.1016/j.bbalip.2025.159647
Simone Serrao , Eleonora Bossi , Vanna Denti , Johannes Burtscher , Martin Faulhaber , Günter Weiss , Wolfgang Schobersberger , Tobias Dünnwald , Giuseppe Paglia
This study investigates the effect of recovery phases in either hyperoxic air or hypoxic air during physical exercise in hypoxia on lipid metabolism in 11 male athletes.
We observed a long-term effect leading to increased plasma triacylglycerols and diacylglycerols, along with a decrease in sphingomyelin when athletes received supplemental oxygen during recovery. In contrast, no significant changes in circulating lipids were detected in athletes trained under hypoxic recovery conditions after 7 days.
We propose that hypoxic exercise induced potentially protective metabolic adaptations that might be disrupted by hyperoxic recovery.
本文研究了11名男运动员在低氧或高氧条件下进行体育锻炼时的恢复阶段对脂质代谢的影响。我们观察到,当运动员在恢复期间接受补充氧气时,血浆三酰甘油和二酰甘油会增加,同时鞘磷脂也会减少。相比之下,在低氧恢复条件下训练7天后,运动员的循环脂质没有明显变化。我们认为,低氧运动诱导了潜在的保护性代谢适应,这种适应可能被高氧恢复所破坏。
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引用次数: 0
Eicosapentaenoic acid inhibits cholesterol efflux pathways from cholesterol-loaded human THP-1 macrophages by reducing the hydrolysis of cholesteryl esters mediated by carboxylesterase 1 二十碳五烯酸通过减少羧酸酯酶1介导的胆固醇酯水解来抑制胆固醇负荷的人THP-1巨噬细胞的胆固醇外排途径。
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-13 DOI: 10.1016/j.bbalip.2025.159646
Maxime Nowak , Hani Dakroub , Benoît Noël , Delphine Rousseau-Ralliard , Sana Slimene , Nathalie Abi-Saleh , Morgane Benardeau , Benoît Vedie , Anne-Marie Cassard , Jean-Louis Paul , Natalie Fournier
A diet high in n-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) (C20:5 n-3), is cardioprotective. PUFAs integrate into membrane phospholipids, altering membrane protein function. We investigated the effects of various PUFAs on the anti-atherogenic cholesterol efflux pathways from cholesterol-loaded human THP-1 macrophages. Cells were supplemented (or not: standard cells) with 70 μM EPA, 50 μM arachidonic acid (AA) (C20:4 n-6) or 15 μM docosahexaenoic acid (DHA) (C22:6 n-3) for an extended duration to simulate a dietary strategy. EPA led to a 13 % decrease in ABCA1-mediated cholesterol efflux and to a 17 % decrease in SR-BI/ABCG1-mediated cholesterol efflux without affecting the expression of efflux proteins, while AA and DHA showed no impact. Compared to standard cells, EPA cells exhibited higher EPA levels along with reduced AA levels. EPA cells showed increased amounts of triglycerides and cholesteryl esters (CE) without a change in the acetylated LDL uptake. EPA did not influence the phenotype of macrophages according to surface markers and released cytokines. The incorporation of EPA did not disrupt efflux in macrophages loaded with free cholesterol. Conversely, EPA decreased CE hydrolysis from lipid droplets by 22 %. The diminished cholesterol efflux was not related to triglyceride accumulation or to variations in apo E secretion. EPA reduced the expression of carboxylesterase 1 (CES1) protein by 17 % without affecting the expression of neutral cholesterol ester hydrolase 1 (NCEH1). In conclusion, the membrane incorporation of EPA hinders the cholesterol efflux pathways in THP-1 foam cells likely by impairing the CE hydrolysis mediated by carboxylesterase 1.
富含n-3多不饱和脂肪酸(PUFAs)的饮食,特别是二十碳五烯酸(EPA) (C20:5 n-3),对心脏有保护作用。PUFAs整合到膜磷脂中,改变膜蛋白功能。我们研究了各种PUFAs对胆固醇负载的人THP-1巨噬细胞抗动脉粥样硬化胆固醇外排途径的影响。细胞被添加(或不添加:标准细胞)70 μM EPA、50 μM花生四烯酸(AA) (C20:4 n-6)或15 μM二十二碳六烯酸(DHA) (C22:6 n-3)较长时间,以模拟饮食策略。EPA导致abca1介导的胆固醇外排减少13 %,SR-BI/ abcg1介导的胆固醇外排减少17 %,而不影响外排蛋白的表达,而AA和DHA没有影响。与标准细胞相比,EPA细胞表现出较高的EPA水平和较低的AA水平。EPA细胞显示甘油三酯和胆固醇酯(CE)的数量增加,但乙酰化LDL的摄取没有变化。根据表面标记物和释放的细胞因子,EPA对巨噬细胞的表型没有影响。EPA的掺入不会破坏装载游离胆固醇的巨噬细胞的外排。相反,EPA使脂滴的CE水解降低了22% %。胆固醇外排减少与甘油三酯积累或载脂蛋白E分泌变化无关。EPA使羧酸酯酶1 (CES1)蛋白的表达降低了17. %,但不影响中性胆固醇酯水解酶1 (NCEH1)的表达。综上所述,EPA的膜掺入可能通过损害羧酸酯酶1介导的CE水解来阻碍THP-1泡沫细胞中的胆固醇外排途径。
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引用次数: 0
Upregulation of the maresin pathway and PGE2 metabolism in the failing human left ventricle 衰竭的人左心室maresin通路和PGE2代谢的上调。
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-12 DOI: 10.1016/j.bbalip.2025.159645
Amel Bouhadoun , Hasanga D. Manikpurage , Gaelle Merheb , Alexandre Boutigny , Marc Dubourdeau , Vincent Baillif , Catherine Deschildre , Marylou Para , Aurélie Sannier , Lydia Deschamps , Benjamin Richard , Benoît Ho-Tin-Noé , Jean-Baptiste Michel , Marianne Abifadel , Jean-Etienne Fabre , Valérie Urbach , Dan Longrois , Xavier Norel
Chronic inflammation is involved in the pathogenesis of heart failure (HF), with cardiac remodeling and fibrosis resulting from sustained myofibroblasts activation. This is due to an imbalance between pro-inflammatory and pro-resolving mediators including specialized pro-resolving lipid mediators (SPM). This study aimed to explore the SPM pathway and its crosstalks with other pathways in human left ventricle (LV) samples from HF-patients and non-HF donors or in ex-vivo cultured cardiac fibroblasts.
The SPM content was measured in LV samples from HF-patients and donors. Resolvin D5 (RvD5) and maresin-1 (MaR1) were the most abundant SPM and with similar levels between both groups, at baseline. Following exposure to exogenous DHA or EPA, SPM levels increased in both groups but MaR1 and 7(S)-MaR1 have shown a significantly higher increase in ex-vivo LV samples from HF-patients compared to donors. Furthermore, we found a higher expression of the related enzymes (lipoxygenases, LOXs): 15-LOX-1, 15-LOX-2 and 12-LOX in HF-patients LV in vitro samples. Finally, the MaR1 receptor (LGR6) expression was also increased in these LV samples from HF-patients compared to donors. In addition, we investigated the role of SPM on COX-2/mPGES-1/prostaglandin E2 (PGE2) pathway previously described as cardioprotective in HF. In cardiac fibroblasts from HF-patients, exposed to inflammatory conditions, RvD1 and MaR1 increased PGE2 biosynthesis while RvD5 decreased it.
Taken together, our data show an enhanced MaR1 biosynthesis and functional pathway in the heart from HF-patients. Furthermore, in cultured cardiac fibroblasts, MaR1 increased the PGE2 concentration levels. These data highlighted novel aspects of inflammation regulation in HF physiopathology.
慢性炎症参与心力衰竭(HF)的发病机制,由持续的肌成纤维细胞激活引起心脏重塑和纤维化。这是由于促炎和促溶解介质之间的不平衡,包括专门的促溶解脂质介质(SPM)。本研究旨在探讨hf患者和非hf供体左心室(LV)样本或离体培养的心脏成纤维细胞中SPM通路及其与其他通路的串扰。在hf患者和供者的LV样品中测量SPM含量。Resolvin D5 (RvD5)和marsin -1 (MaR1)是最丰富的SPM,在基线时两组之间的水平相似。暴露于外源性DHA或EPA后,两组的SPM水平均升高,但与供体相比,来自hf患者的离体LV样本中MaR1和7(S)-MaR1的升高明显更高。此外,我们发现相关酶(脂氧合酶,LOXs): 15-LOX-1, 15-LOX-2和12-LOX在hf患者LV体外样品中表达较高。最后,与供体相比,来自hf患者的LV样本中的MaR1受体(LGR6)表达也有所增加。此外,我们研究了SPM对COX-2/mPGES-1/前列腺素E2 (PGE2)途径的作用,该途径之前被认为是HF的心脏保护作用。在hf患者的心脏成纤维细胞中,暴露于炎症条件下,RvD1和MaR1增加了PGE2的生物合成,而RvD5则降低了PGE2的生物合成。综上所述,我们的数据显示hf患者心脏中MaR1的生物合成和功能途径增强。此外,在培养的心脏成纤维细胞中,MaR1增加了PGE2的浓度水平。这些数据突出了心衰生理病理中炎症调节的新方面。
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引用次数: 0
A natural thiophene from Eclipta prostrata (L.) combats obesity by enhancing adipocytes thermogenesis in high-fat diet-fed obese mice 一种来自黄竹的天然噻吩(L.)通过增强高脂肪饮食喂养的肥胖小鼠的脂肪细胞产热来对抗肥胖
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-10 DOI: 10.1016/j.bbalip.2025.159644
Xiaochun Zhang, Chunhua Lu, Yuemao Shen
The rising global prevalence of obesity has become a serious public health concern. Recent studies have revealed that natural products derived from medicinal plants can activate adipocytes thermogenesis, presenting promising therapeutic strategies for obesity management. Eclipta prostrata (L.) L., traditionally used for regulating blood glucose and lipid metabolism, has recently emerged as a potential anti-obesity herb. In this study, we identified 2,2′:5′,2″-terthiophene-5-carboxylic acid (T-CA), a naturally occurring thiophene derivative isolated from Eclipta prostrata, as a novel anti-obesity candidate. It enhanced thermogenesis in adipose tissue, effectively preventing and ameliorating high-fat diet (HFD)-induced obesity in mice while mitigating glucose and lipid dysregulation. Mechanistically, T-CA upregulated Perilipin 5 (Plin5), which in turn activated the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling pathway and reinforced lipid droplet (LD)–mitochondria coupling. These coordinated actions promoted mitochondrial biogenesis and fatty acid oxidation, thereby improving systemic metabolic homeostasis and enhancing resistance to diet-induced obesity. To summarize, T-CA represents an appealing approach for treating HFD-induced obesity by augmenting thermogenesis through mitochondrial activation and LD-mitochondria interactions.
全球肥胖率的上升已成为一个严重的公共卫生问题。近年来的研究表明,从药用植物中提取的天然产物可以激活脂肪细胞产热,为肥胖管理提供了有希望的治疗策略。黄花(L.)传统上用于调节血糖和脂质代谢的L.最近出现了一种潜在的抗肥胖草药。在这项研究中,我们鉴定了2,2 ':5 ',2″- terthiphene -5-carboxylic acid (T-CA),这是一种天然存在的从黄竹中分离的噻吩衍生物,作为一种新的抗肥胖候选药物。它增强了脂肪组织的产热作用,有效地预防和改善了高脂肪饮食(HFD)诱导的小鼠肥胖,同时减轻了葡萄糖和脂质失调。从机制上说,T-CA上调了Perilipin 5 (Plin5),从而激活了amp活化的蛋白激酶(AMPK)/过氧化物酶体增殖体活化受体γ辅助激活因子1- α (PGC-1α)信号通路,并增强了脂滴(LD) -线粒体偶联。这些协同作用促进线粒体生物发生和脂肪酸氧化,从而改善全身代谢稳态,增强对饮食性肥胖的抵抗力。总之,T-CA代表了一种通过线粒体激活和ld -线粒体相互作用增加产热作用来治疗hfd诱导的肥胖的有吸引力的方法。
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引用次数: 0
The role of ancient ubiquitous protein 1 (Aup1) in regulating hepatic lipid droplet levels, endoplasmic reticulum stress, and inflammation in zebrafish (Danio rerio) 古泛在蛋白1 (Aup1)在调节斑马鱼肝脂滴水平、内质网应激和炎症中的作用。
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-06 DOI: 10.1016/j.bbalip.2025.159643
Shuangyang Xu , Yanan Shen , Zengqi Zhao , Kangsen Mai , Qinghui Ai
Excessive supplementation of palm oil (PO) in aquafeeds induces hepatic endoplasmic reticulum (ER) stress and inflammatory responses in fish, while lipid droplet (LD) formation has been demonstrated to alleviate stress and inflammation by sequestering lipotoxic lipids. Studies in mammals indicate that ancient ubiquitous protein 1 (Aup1) is a LD-associated protein participating in ER-associated degradation (ERAD) and LD regulation. However, whether Aup1 is involved in the regulation of hepatic LD metabolism, ER stress, and inflammatory responses has not been elucidated in fish. In this study, we cloned zebrafish (Danio rerio) aup1, conducted sequence analysis, and established in vitro hepatocyte models with Aup1 overexpression and knockdown through electroporation of plasmids. Bioinformatics analysis identified zebrafish Aup1 as an unstable, alkaline, hydrophilic transmembrane protein. Subcellular localization demonstrated dual localization of Aup1 on LDs and the ER. Tissue distribution experiments revealed Aup1 was ubiquitously expressed in multiple tissues, with the highest expression in the liver. RT-qPCR and Western blot showed that PO significantly upregulated Aup1 expression in vivo and in vitro, and dual-luciferase reporter assays identified Atf4a as an important transcriptional activator of zebrafish aup1 promoter. Aup1 overexpression markedly improved LD levels as well as triglyceride (TG) content, and reduced ER stress-related genes and pro-inflammatory cytokines expression in zebrafish liver (ZFL) cells. Conversely, Aup1 knockdown exerted opposite effects. These findings indicated that Aup1 could promote LD biogenesis and mitigate ER stress and inflammation. This study may provide novel insights for developing therapeutic strategies against PO-induced hepatic damage in cultured fish species.
在水产饲料中过量添加棕榈油(PO)会引起鱼的肝内质网(ER)应激和炎症反应,而脂滴(LD)的形成已被证明可以通过隔离脂毒性脂质来缓解应激和炎症。在哺乳动物中的研究表明,古泛在蛋白1 (Aup1)是一种LD相关蛋白,参与er相关降解(ERAD)和LD调控。然而,在鱼类中,Aup1是否参与肝脏LD代谢、内质网应激和炎症反应的调节尚不清楚。在本研究中,我们克隆了斑马鱼(Danio rerio)的aup1,进行了序列分析,并通过电穿孔质粒建立了aup1过表达和敲低的体外肝细胞模型。生物信息学分析表明,斑马鱼Aup1是一种不稳定的碱性亲水性跨膜蛋白。亚细胞定位显示了Aup1在ld和ER上的双重定位。组织分布实验显示,Aup1在多种组织中普遍表达,在肝脏中表达量最高。RT-qPCR和Western blot结果显示,PO在体内和体外均显著上调Aup1的表达,双荧光素酶报告基因检测发现Atf4a是斑马鱼Aup1启动子的重要转录激活因子。过表达Aup1可显著提高斑马鱼肝脏(ZFL)细胞的LD水平和甘油三酯(TG)含量,降低内质网应激相关基因和促炎细胞因子的表达。相反,敲低Aup1会产生相反的效果。这些结果表明,Aup1可以促进LD的生物发生,减轻内质网应激和炎症。该研究可能为开发抗po诱导的养殖鱼类肝损伤的治疗策略提供新的见解。
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引用次数: 0
Tumor necrosis factor alpha-induced activation of SREBP2 promotes cholesterol biosynthesis in cholestasis 肿瘤坏死因子α诱导的SREBP2激活促进胆固醇淤积的生物合成
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-06 DOI: 10.1016/j.bbalip.2025.159642
Ziqian Xu , Xinyu Cao , Zhixian Zhu, Jiaxin Lei, Ling Li, Xiaoxun Zhang, Jin Chai

Background and aims

Cholestasis is frequently associated with lipid metabolism disorders, elevated cholesterol levels and disruptions in bile acid homeostasis. Nevertheless, the mechanisms underlying cholesterol elevation in cholestasis remain inadequately understood. This study aims to investigate alterations in cholesterol levels and potential mechanisms in mouse models of cholestasis. Additionally, we evaluate the therapeutic potential of Sterol Regulatory Element Binding Protein 2 (SREBP2), a key transcription factor regulating cholesterol synthesis, in treating cholestasis.

Approaches and results

We developed mouse models of cholestasis using bile duct ligation (BDL) and a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Serum and liver samples were collected for analysis. The human hepatoma cell line PLC/RPF/5 was used for mechanistic studies. Cholestatic mice exhibited significantly elevated total cholesterol levels in serum and liver. Gene expression analysis revealed marked upregulation of cholesterol biosynthesis-related genes and the transcription factor SREBP2. Mechanistic studies indicated that TNFα promotes cholesterol synthesis by activating SREBP2 and its downstream target genes. To validate these findings in vivo, we employed the BDL mouse model and treated the mice with Fatostatin, a known SREBP2 inhibitor. Administration of Fatostatin significantly reduced serum ALT, ALP and hepatic cholesterol levels in the BDL mouse model, suggesting a potential therapeutic effect against cholestatic liver injury.

Conclusions

This study concludes that the activation of the NF-κB signaling pathway by TNFα leads to increased expression of SREBP2 in cholestatic mouse model. These findings indicate that the TNFα/NF-κB/SREBP2 pathway could serve as a promising target for treating cholestasis.
背景和目的胆汁淤积通常与脂质代谢紊乱、胆固醇水平升高和胆汁酸稳态破坏有关。然而,胆固醇升高的机制在胆汁淤积症中仍未得到充分的了解。本研究旨在探讨小鼠胆汁淤积模型中胆固醇水平的改变及其潜在机制。此外,我们评估了甾醇调节元件结合蛋白2 (SREBP2)在治疗胆汁淤积中的治疗潜力,SREBP2是调节胆固醇合成的关键转录因子。方法和结果我们采用胆管结扎(BDL)和0.1% 3,5-二氧羰基-1,4-二氢碰撞碱(DDC)饮食建立了胆汁淤积小鼠模型。采集血清和肝脏样本进行分析。采用人肝癌细胞株PLC/RPF/5进行机制研究。胆汁淤积小鼠血清和肝脏中总胆固醇水平显著升高。基因表达分析显示胆固醇生物合成相关基因和转录因子SREBP2显著上调。机制研究表明TNFα通过激活SREBP2及其下游靶基因促进胆固醇合成。为了在体内验证这些发现,我们采用了BDL小鼠模型,并用Fatostatin(一种已知的SREBP2抑制剂)治疗小鼠。在BDL小鼠模型中,给予Fatostatin可显著降低血清ALT、ALP和肝脏胆固醇水平,提示其对胆汁淤积性肝损伤具有潜在的治疗作用。结论TNFα激活NF-κB信号通路可导致胆汁淤积小鼠模型中SREBP2的表达升高。这些发现表明,TNFα/NF-κB/SREBP2通路可能是治疗胆汁淤积的一个有希望的靶点。
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引用次数: 0
Advances in lipid research: From bench to bedside 脂质研究的进展:从实验室到床边:第63届国际脂质生物科学会议的特刊。
IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-06-01 DOI: 10.1016/j.bbalip.2025.159624
Gwendolyn Barceló-Coblijn , Jesús Balsinde
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引用次数: 0
期刊
Biochimica et biophysica acta. Molecular and cell biology of lipids
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