Pub Date : 2025-06-18DOI: 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。
{"title":"Altered levels of sphingomyelins, ceramides, glycerophospholipids, and diacylglycerols in thymoma tissues","authors":"Jie Zhang , Xiaoling Zang , Wei Meng , Peng Jiao , Jiangyu Wu , Lizhen Zhao , Zhuangzhuang Li , Xin Zhang , Huanhuan Yang , Zhihua Lv","doi":"10.1016/j.bbalip.2025.159650","DOIUrl":"10.1016/j.bbalip.2025.159650","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159650"},"PeriodicalIF":3.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Cold-sensitive pathway elongates a non-native cis-7-hexadecenoic acid to cis-9-octadecenoic acid in the cyanobacterium Synechocystis sp. PCC 6803","authors":"Asuka Kobayashi , Nattiwong Pankasem , Kotaro Kobayashi , Florence Corellou , Kohei Yoneda , Yoshiaki Maeda , Iwane Suzuki","doi":"10.1016/j.bbalip.2025.159649","DOIUrl":"10.1016/j.bbalip.2025.159649","url":null,"abstract":"<div><div>Cellular membranes of the cyanobacterium <em>Synechocystis</em> sp. PCC 6803 primarily consist of glycerolipids esterified unsaturated C18 and saturated C16 fatty acids (FAs). We introduced the <em>Ot17.2</em> gene from the Mamiellophyceae <em>Ostreococcus tauri</em> into <em>Synechocystis</em>. The cells, <em>Ot17.2</em>+, produced <em>cis</em>-7-hexadecenoic acid (hypogeic acid, 16:1∆7) at the half level of the total C16 FAs, suggesting that the <em>Ot17.2</em> 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 <em>desC</em> gene for C18-specific ∆9 desaturase, producing <em>cis</em>-9-octadecenoic acid (oleic acid, 18:1∆9) in the <em>Ot17.2</em>+ strain. Surprisingly, the <em>desC</em> gene was entirely deleted in the <em>Ot17.2</em>+/<em>desC</em>- strain, despite the knowledge that the <em>desC</em> 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 <em>desC</em> gene completely in the cells expressing the <em>desC2</em> gene for the C16 specific ∆9 desaturase, producing <em>cis</em>-9-hexadecenoic acid (palmitoleic acid, 16:1∆9). These findings indicate that <em>Synechocystis</em> may synthesize 18:1∆9 from 16:1∆7 via FA elongation, and <em>cis</em>-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 (<em>Ot17.2</em>+/<em>desC</em>- 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 <em>Ot17.2</em>+/<em>desC</em>- supported the growth, suggesting that the lipase activity involved in the FA salvage and elongation system might be severely sensitive to low temperatures.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159649"},"PeriodicalIF":3.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-16DOI: 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.
{"title":"Adcy8 deficiency contributes to impaired lipolysis and an increased prevalence of obesity in mice","authors":"Mengxue Han , Qing Shu , Ruili Yu , Shaohong Wu , Handan Deng , Yang Liu , Quan Yu , Wei Li , Luyang Gao , Yawen Zhao , Geyang Xu","doi":"10.1016/j.bbalip.2025.159648","DOIUrl":"10.1016/j.bbalip.2025.159648","url":null,"abstract":"<div><div>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 <em>Adcy8</em> knockout (<em>Adcy8</em><sup><em>−/−</em></sup>) 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 <em>Adcy8</em><sup><em>−/−</em></sup> 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.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159648"},"PeriodicalIF":3.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-14DOI: 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.
{"title":"Hyperoxic recovery impacts on metabolic adaptations induced by hypoxic exercise: A lipidomics approach","authors":"Simone Serrao , Eleonora Bossi , Vanna Denti , Johannes Burtscher , Martin Faulhaber , Günter Weiss , Wolfgang Schobersberger , Tobias Dünnwald , Giuseppe Paglia","doi":"10.1016/j.bbalip.2025.159647","DOIUrl":"10.1016/j.bbalip.2025.159647","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>We propose that hypoxic exercise induced potentially protective metabolic adaptations that might be disrupted by hyperoxic recovery.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159647"},"PeriodicalIF":3.9,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-13DOI: 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.
{"title":"Eicosapentaenoic acid inhibits cholesterol efflux pathways from cholesterol-loaded human THP-1 macrophages by reducing the hydrolysis of cholesteryl esters mediated by carboxylesterase 1","authors":"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","doi":"10.1016/j.bbalip.2025.159646","DOIUrl":"10.1016/j.bbalip.2025.159646","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159646"},"PeriodicalIF":3.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-12DOI: 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.
{"title":"Upregulation of the maresin pathway and PGE2 metabolism in the failing human left ventricle","authors":"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","doi":"10.1016/j.bbalip.2025.159645","DOIUrl":"10.1016/j.bbalip.2025.159645","url":null,"abstract":"<div><div>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 <em>ex-vivo</em> cultured cardiac fibroblasts.</div><div>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(<em>S</em>)-MaR1 have shown a significantly higher increase in <em>ex-vivo</em> 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 <em>in vitro</em> 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 E<sub>2</sub> (PGE<sub>2</sub>) pathway previously described as cardioprotective in HF. In cardiac fibroblasts from HF-patients, exposed to inflammatory conditions, RvD1 and MaR1 increased PGE<sub>2</sub> biosynthesis while RvD5 decreased it.</div><div>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 PGE<sub>2</sub> concentration levels. These data highlighted novel aspects of inflammation regulation in HF physiopathology.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159645"},"PeriodicalIF":3.9,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-10DOI: 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.
{"title":"A natural thiophene from Eclipta prostrata (L.) combats obesity by enhancing adipocytes thermogenesis in high-fat diet-fed obese mice","authors":"Xiaochun Zhang, Chunhua Lu, Yuemao Shen","doi":"10.1016/j.bbalip.2025.159644","DOIUrl":"10.1016/j.bbalip.2025.159644","url":null,"abstract":"<div><div>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. <em>Eclipta prostrata</em> (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 <em>Eclipta prostrata</em>, 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.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159644"},"PeriodicalIF":3.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-06DOI: 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.
{"title":"The role of ancient ubiquitous protein 1 (Aup1) in regulating hepatic lipid droplet levels, endoplasmic reticulum stress, and inflammation in zebrafish (Danio rerio)","authors":"Shuangyang Xu , Yanan Shen , Zengqi Zhao , Kangsen Mai , Qinghui Ai","doi":"10.1016/j.bbalip.2025.159643","DOIUrl":"10.1016/j.bbalip.2025.159643","url":null,"abstract":"<div><div>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 (<em>Danio rerio</em>) <em>aup1</em>, conducted sequence analysis, and established <em>in vitro</em> 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 <em>in vivo</em> and <em>in vitro</em>, and dual-luciferase reporter assays identified Atf4a as an important transcriptional activator of zebrafish <em>aup1</em> 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.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159643"},"PeriodicalIF":3.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-06DOI: 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.
{"title":"Tumor necrosis factor alpha-induced activation of SREBP2 promotes cholesterol biosynthesis in cholestasis","authors":"Ziqian Xu , Xinyu Cao , Zhixian Zhu, Jiaxin Lei, Ling Li, Xiaoxun Zhang, Jin Chai","doi":"10.1016/j.bbalip.2025.159642","DOIUrl":"10.1016/j.bbalip.2025.159642","url":null,"abstract":"<div><h3>Background and aims</h3><div>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.</div></div><div><h3>Approaches and results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 6","pages":"Article 159642"},"PeriodicalIF":3.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144239789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.bbalip.2025.159624
Gwendolyn Barceló-Coblijn , Jesús Balsinde
{"title":"Advances in lipid research: From bench to bedside","authors":"Gwendolyn Barceló-Coblijn , Jesús Balsinde","doi":"10.1016/j.bbalip.2025.159624","DOIUrl":"10.1016/j.bbalip.2025.159624","url":null,"abstract":"","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 5","pages":"Article 159624"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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