Journal of Lipid Research最新文献

Liver-specific Nr1h4 deletion in mice with human-like bile acid composition causes severe liver injury. 具有人样胆汁酸组成的小鼠肝脏特异性Nr1h4缺失导致严重的肝损伤。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-09 DOI: 10.1016/j.jlr.2025.100839

Yusuke Mishima, Kota Tsuruya, Kinuyo Ida, Satsuki Ieda, Yutaka Inagaki, Akira Honda, Tatehiro Kagawa, Akihide Kamiya

{"title":"Liver-specific Nr1h4 deletion in mice with human-like bile acid composition causes severe liver injury.","authors":"Yusuke Mishima, Kota Tsuruya, Kinuyo Ida, Satsuki Ieda, Yutaka Inagaki, Akira Honda, Tatehiro Kagawa, Akihide Kamiya","doi":"10.1016/j.jlr.2025.100839","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100839","url":null,"abstract":"The farnesoid X receptor, encoded by NR1H4, is crucial for bile acid, lipid, and glucose metabolism. NR1H4 mutations in humans cause a severe liver injury called progressive familial intrahepatic cholestasis 5. However, Nr1h4 deletion in mice did not cause severe liver damage at a young age, likely because of the higher levels of hydrophilic bile acids synthesized by the mouse-specific bile acid metabolic enzymes Cyp2a12 and Cyp2c70. We aimed to assess hepatic NR1H4 function by taking advantage of the recently established Cyp2a12/Cyp2c70 double-knockout (CYPDKO) mouse model, which has a human-like bile acid composition containing mainly hydrophobic bile acids. Liver-specific Nr1h4-deficient CYPDKO mice were established using an adeno-associated virus-derived genome-editing method. Nr1h4-deficient wild-type (WT) mice showed no significant changes in marker levels for serum liver injury. In contrast, Nr1h4-deficient CYPDKO mice showed an increase in the liver/body weight ratio and serum liver injury markers, suggesting that the combination of human-like bile acid composition and Nr1h4 deletion induces liver injury. Nr1h4 deletion increased total bile acid levels in the liver through the upregulation of bile acid metabolic genes and downregulation of bile acid transporters. Conversely, overexpression of a small heterodimer partner (SHP), a downstream gene of Nr1h4, suppresses liver injury induced by Nr1h4 deletion in CYPDKO mice. Overall, liver-specific Nr1h4 deficiency induced significant liver damage in mice with human-like bile acids, unlike in WT mice, validating its use as a new animal model for cholestatic liver disease. Therefore, SHP may be a potential target for the treatment of cholestasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100839"},"PeriodicalIF":5.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates. 营养过剩小鼠肝脏新生脂肪生成的升高依赖于多种基质。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-09 DOI: 10.1016/j.jlr.2025.100838

Jordan W Strober, Stephan Siebel, Susan F Murray, Manuel González Rodríguez, Carlos Rodriguez-Navas Gonzalez, Daniel F Vatner

{"title":"Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates.","authors":"Jordan W Strober, Stephan Siebel, Susan F Murray, Manuel González Rodríguez, Carlos Rodriguez-Navas Gonzalez, Daniel F Vatner","doi":"10.1016/j.jlr.2025.100838","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100838","url":null,"abstract":"Increased de novo lipogenesis (DNL) contributes to hyperlipidemia, MASLD, and ASCVD in insulin resistant subjects. However, multiple pathways support lipogenesis and few have sought to quantify the contributions of the discrete metabolic pathways that contribute to lipogenesis. In this study, antisense oligonucleotides (ASOs) targeting glucokinase (Gck), lactate dehydrogenase A (Ldha), and glutamic-pyruvic transaminase 2 (Gpt2) were utilized to restrict substrate flux from lipogenic precursors in C57BL6/J mice, comparing controls (CO) and chronic overnutrition (ON). In CO mice, ASO treatments did not significantly alter lipogenesis; however, there was a trend toward decreased hepatic triglyceride content and DNL, especially with the GPT2 ASO (TG=-46.8%; DNL=-53.7%). Expectedly, increased hepatic TG content and DNL (ON vs CO: TG=+187.9%; DNL=+41.8%) was observed in mice with chronic overnutrition. Gas chromatography-mass spectrometry analyses demonstrated increased hepatic TCA cycle metabolites (ON vs CO: fumarate +74.2%; malate +54.0%; and citrate +43.2) and decreased hepatic concentrations of multiple amino acids (ON vs CO: Leu -41.7%; Ile -45.0%; Val -56.3%; Ser -22.6%). With ON, TG content and DNL were reduced by restricting lipogenic carbon entry from alanine (GPT2: TG=-45.5%; DNL=-48.1%), lactate (LDHA: TG=-25.8%; DNL=-33.1%), or glucose (GCK: TG=-59.2%; DNL=-69.2%). Amino acids appear to be a consistent carbon source for DNL in mice; however, carbon entry from all sources is required to maintain the significantly elevated rates of hepatic DNL in chronically overfed mice. These findings may inform the development of novel therapies and underscore the importance of peripheral substrate storage and oxidation in the prevention of dyslipidemia in the metabolic syndrome.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100838"},"PeriodicalIF":5.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Helminth-induced prostaglandin signalling and dietary shifts in PUFA metabolism promote colitis-associated cancer. 蠕虫诱导的前列腺素信号和PUFA代谢的饮食变化促进了结肠炎相关的癌症。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-07 DOI: 10.1016/j.jlr.2025.100837

Katherine A Smith, Ella K Reed, Irina Guschina, Victoria J Tyrrell, Claire Butters, Matthew G Darby, Brunette Katsandegwaza, Alisha Chetty, William Gc Horsnell, Valerie B O'Donnell, Awen Gallimore

{"title":"Helminth-induced prostaglandin signalling and dietary shifts in PUFA metabolism promote colitis-associated cancer.","authors":"Katherine A Smith, Ella K Reed, Irina Guschina, Victoria J Tyrrell, Claire Butters, Matthew G Darby, Brunette Katsandegwaza, Alisha Chetty, William Gc Horsnell, Valerie B O'Donnell, Awen Gallimore","doi":"10.1016/j.jlr.2025.100837","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100837","url":null,"abstract":"Oxylipins derived from dietary polyunsaturated fatty acids (PUFAs) are key determinants of intestinal health, homeostasis and inflammatory disorders, such as colitis-associated colorectal cancer (CAC). Previous research has independently linked a high dietary omega (ω)-6:ω-3 PUFA ratio, or intestinal helminth infection, to an increased risk of CAC. However, whether these two factors interact to exacerbate disease risk and whether oxylipins contribute to this is unknown. In this study, we report that infection with the helminth Heligmosomoides polygyrus bakeri (Hpb) exacerbates tumour formation when combined with a high ω-6:ω-3 PUFA ratio diet. Dietary increases in tumour burden correlated with heightened levels of arachidonic acid (AA) and AA-derived lipoxygenase (LOX) oxylipins in the colon, including the 12/15-LOX product 12-hydroxyeicosatetraenoic acid, prior to disease onset. Although helminth infection further increased the production of 12/15-LOX oxylipins and increased expression of Alox15, responsible for producing these metabolites, inhibition of cyclooxygenase-dependent prostaglandin production with aspirin prevented helminth-exacerbation of disease. Helminth-infected mice exhibited increased phosphorylation of β-catenin in the colon, which was inhibited by EP2 and 4 antagonists. Moreover, administration of an EP agonist increased tumour burden in naive mice fed a high ω-6:ω-3 PUFA ratio diet, to the levels seen in helminth-exacerbation of disease. These data suggest that dietary changes in fatty acid composition coordinate with helminth-induced activation of EP signalling to exacerbate tumour development.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100837"},"PeriodicalIF":5.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting to High-Density Lipoprotein Cholesterol: New Insights for Inflammatory Bowel Disease Treatment. 靶向高密度脂蛋白胆固醇：炎症性肠病治疗的新见解

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-06 DOI: 10.1016/j.jlr.2025.100836

Xiaotong Wang, Xuefei Li, Kezhen Liu, Ke Yi, Yang Yang, Dongwen Wu, Xiaowei Liu

{"title":"Targeting to High-Density Lipoprotein Cholesterol: New Insights for Inflammatory Bowel Disease Treatment.","authors":"Xiaotong Wang, Xuefei Li, Kezhen Liu, Ke Yi, Yang Yang, Dongwen Wu, Xiaowei Liu","doi":"10.1016/j.jlr.2025.100836","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100836","url":null,"abstract":"Background: The anti-inflammatory and vasoprotective properties of high-density lipoprotein cholesterol (HDL-C) make it best known in cardiovascular disease and sepsis. We aimed to investigate whether interventions that target HDL-C metabolism may be used for the prevention and treatment of inflammatory bowel disease (IBD).Methods: The relationship between serum lipids and IBD clinical manifestations were analyzed in both respective and prospective cohort. Later, therapeutic effect and mechanism of cholesteryl ester transfer protein inhibitors (CETPi) in IBD treatment were explored by in vivo experiments.Findings: IBD patients had significantly reduced HDL-C, which was negatively correlated with their inflammatory status. Furthermore, HDL-C level was elevated by biologics agents and HDL-C concentration pre-treatment was predictive for IBD patients' future disease severity. Elevating HDL-C by CETPi before or even after the onset of experimental colitis reduced disease severity, which is associated with an ATF3-dependent anti-inflammatory reprogramming of macrophages and with enhanced gut barrier function.Interpretation: Together, these results demonstrate an important role of HDL-C in IBD and indicate the potential pharmacological effects of CETPi for future IBD therapy through elevation of HDL-C.Funding: This study was supported by the National Natural Science Foundation of China (No. 82200590 to D.W., No. 82230019 and No.82341225 to X.L.) and Natural Science Foundation of Hunan Province (No. 2023JJ20097 and No. 2022JJ40823 to D.W.).","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100836"},"PeriodicalIF":5.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Creb3l3 deficiency promotes intestinal lipid accumulation and alters ApoB-containing lipoprotein kinetics. Creb3l3缺乏促进肠道脂质积累并改变载脂蛋白动力学。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-05-29 DOI: 10.1016/j.jlr.2025.100833

Darby W Sweeney, Meng-Chieh Shen, Steven A Farber

{"title":"Creb3l3 deficiency promotes intestinal lipid accumulation and alters ApoB-containing lipoprotein kinetics.","authors":"Darby W Sweeney, Meng-Chieh Shen, Steven A Farber","doi":"10.1016/j.jlr.2025.100833","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100833","url":null,"abstract":"Elevated levels of triglycerides in the bloodstream, a condition known as hypertriglyceridemia, represent a significant risk factor for the development of metabolic disorders and cardiovascular diseases. One key regulator of lipid metabolism is the transcription factor Creb3l3, which is expressed in the liver, intestine, and adipose tissue. Creb3l3 is localized to the endoplasmic reticulum (ER) membrane, and in vertebrates plays a crucial role in plasma lipid homeostasis. However, the precise molecular mechanisms underlying Creb3l3's influence on cellular lipid metabolism remains undefined. To address this knowledge gap, we generated zebrafish mutants lacking both creb3l3 orthologs (creb3l3a and creb3l3b). Gene expression analysis revealed that key creb3l3 target genes, such as apoC2 and apoA4, were significantly downregulated in the intestines of these double mutants. Using two zebrafish lipoprotein reporter lines we assessed lipoprotein dynamics in creb3l3 mutants. Despite producing similar total levels of lipoproteins, creb3l3 mutants exhibited impaired lipoprotein turnover, suggesting a disruption in circulating lipid clearance. Additionally, histological analysis showed an accumulation of intestinal lipids, characterized by an increased number and size of enterocyte lipid droplets. These findings indicate that creb3l3 is essential for regulating postprandial lipid flux in enterocytes through altering the balance between lipid storage and secretion. Our study highlights a critical unappreciated role of Creb3l3 in maintaining intestinal lipid homeostasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100833"},"PeriodicalIF":5.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hepatoprotective drug screening identifies daclatasvir a promising therapeutic candidate for MASLD by targeting PLIN2. 肝保护药物筛选通过靶向PLIN2确定daclatasvir是一种有希望的MASLD治疗候选者。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-05-29 DOI: 10.1016/j.jlr.2025.100835

Rui Shu, Song Tian, Weiyi Qu, Jinjie Yang, Wei Shi, Xinyan Li, Toujun Zou, Changjin Jiang, Yuxuan Zhang, Zifeng Yang, Han Tian, Hailong Yang, Jiajun Fu, Zhi-Gang She, Hongliang Li, Xiao-Jing Zhang

{"title":"Hepatoprotective drug screening identifies daclatasvir a promising therapeutic candidate for MASLD by targeting PLIN2.","authors":"Rui Shu, Song Tian, Weiyi Qu, Jinjie Yang, Wei Shi, Xinyan Li, Toujun Zou, Changjin Jiang, Yuxuan Zhang, Zifeng Yang, Han Tian, Hailong Yang, Jiajun Fu, Zhi-Gang She, Hongliang Li, Xiao-Jing Zhang","doi":"10.1016/j.jlr.2025.100835","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100835","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) has become global health challenges with limited therapeutic strategy. Here, the present study aims to identify promising drug candidates for MASH and to clarify their pharmacological mechanism. By an extensive screening of FDA-approved hepatoprotective medicines using a PA/OA-stimulated hepatocytes model, we identified daclatasvir showing potent anti-MASH capacity against hepatic steatosis deposition and inflammatory response. The hepatoprotective benefits of daclatasvir was further validated in MASH mouse models, induced by a high-fat high-cholesterol (HFHC) diet for 16 weeks or a methionine-choline-deficient (MCD) diet for 4 weeks, as supported by markedly improved histopathological characteristics, serum biochemical level, and transcriptomic analyses. Using the molecular docking assay followed by isothermal titration calorimetry confirmation, we identified that daclatasvir functions as a new perilipin-2 (PLIN2) inhibitor by interrupting its stability. In specific, PLIN2 subjected to MARCH6-mediated protein degradation in a K11-type ubiquitination. Daclatasvir can directly bind to PLIN2 and enhance its interaction with MARCH6, leading to markedly strengthened PLIN2 ubiquitinational degradation and the subsequent decline in lipid droplet disintegration and lipotoxicity. The specific mutation at the binding amino acid sites of PLIN2 with daclatasvir largely abolished the anti-MASH benefit of daclatasvir. In conclusion, the findings of our present study for the first time identified the anti-HCV drug daclatasvir as a novel and potent PLIN2 protein degradant for MASH protection.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100835"},"PeriodicalIF":5.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects. 神经酰胺合成酶2缺失小鼠的深层鞘脂组学和代谢组学分析揭示了复杂的通路特异性作用。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-05-29 DOI: 10.1016/j.jlr.2025.100832

Jeongah Oh, Sneha Muralidharan, Qing Zhao, Johannes Scholz, Iris D Zelnik, Shani Blumenreich, Tammar Joseph, Tamir Dingjan, Pradeep Narayanaswamy, Hyungwon Choi, Heiko Hayen, Federico Torta, Anthony H Futerman

{"title":"Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects.","authors":"Jeongah Oh, Sneha Muralidharan, Qing Zhao, Johannes Scholz, Iris D Zelnik, Shani Blumenreich, Tammar Joseph, Tamir Dingjan, Pradeep Narayanaswamy, Hyungwon Choi, Heiko Hayen, Federico Torta, Anthony H Futerman","doi":"10.1016/j.jlr.2025.100832","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100832","url":null,"abstract":"The sphingolipidome contains thousands of structurally distinct sphingolipid (SL) species. This enormous diversity is generated by the combination of different long-chain-bases (LCBs), N-acyl chains and head groups. In mammals, LCBs are N-acylated with different fatty acids (from C14 to C32, with different degrees of saturation) by six ceramide synthases (CerS1-6) to generate dihydroceramides (DHCer), with each CerS exhibiting specificity towards acyl-Coenzyme As of defined chain length. CerS2 synthesizes very-long-chain (VLC) DHCer, and mice in which CerS2 has been deleted display a number of pathologies. We now expand previous analyses of the mouse sphingolipidome by examining 264 individual SL species in 18 different tissues, building an extensive SL tissue atlas of wild type and CerS2 null mice. While many of the changes in SL levels were similar to those reported earlier, a number of unexpected findings in CerS2 null mouse tissues were observed, such as the decrease in ceramide 1-phosphate levels in the brain, the increase in C26-SL levels in the lung and no changes in levels of ceramides containing t18:0-LCBs (phytosphinganine). Furthermore, analysis of levels of other metabolites revealed changes in at least six major metabolic pathways, including some that impinge upon the SL metabolism. Together, these data highlight the complex changes that occur in the lipidome and metabolome upon depletion of CerS2, indicating how sphingolipids are connected to many other pathways and that care must be taken when assigning a relationship between tissue pathology and one or other specific SL species.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100832"},"PeriodicalIF":5.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial Calcium Uniporter is Required for Thermogenic Adaptation Mediated by Reactive Oxygen Species Signaling. 活性氧信号介导的热适应需要线粒体钙单转运体。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-05-29 DOI: 10.1016/j.jlr.2025.100834

Suji Kim, Seung-Kuy Cha, Kyu-Sang Park, Jun Namkung

{"title":"Mitochondrial Calcium Uniporter is Required for Thermogenic Adaptation Mediated by Reactive Oxygen Species Signaling.","authors":"Suji Kim, Seung-Kuy Cha, Kyu-Sang Park, Jun Namkung","doi":"10.1016/j.jlr.2025.100834","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100834","url":null,"abstract":"Mitochondrial Ca2+ influx via mitochondrial calcium uniporter (MCU) accelerates mitochondrial biogenesis and energy metabolism. Nevertheless, the molecular mechanism of MCU-dependent mitochondrial activation and thermogenesis in thermogenic adipose tissues remains elusive. In this study, we demonstrate that MCU governs mitochondrial functions in brown and beige adipocytes via the formation of mitochondrial reactive oxygen species (mtROS). Mice with a brown adipose tissue-specific Mcu knockout (Mcu BKO) mice exhibited decreased oxygen consumption and heat production, accompanied by downregulation of genes related to β-oxidation and thermogenesis. Furthermore, Mcu BKO mice, exhibiting a reduction in mtROS, showed defective thermogenic responses to cold exposure or β-adrenergic stimulation. Downregulation of thermogenic genes including Ucp1 in Mcu BKO mice can be rescued by exogenous ROS through AMP-activated protein kinase (AMPK) activation. Collectively, our results suggest that MCU modulates mtROS formation, which in turn mediates mitonuclear signaling to cellular response with mitochondrial activation.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100834"},"PeriodicalIF":5.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conjugated bile acids are elevated in severe calcific aortic valve stenosis. 共轭胆汁酸在严重钙化性主动脉瓣狭窄时升高。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-05-21 DOI: 10.1016/j.jlr.2025.100830

Hannah Zhang, Negar Atefi, Arun Surendran, Jun Han, David R Goodlett, Davinder S Jassal, Ashish Shah, Amir Ravandi

{"title":"Conjugated bile acids are elevated in severe calcific aortic valve stenosis.","authors":"Hannah Zhang, Negar Atefi, Arun Surendran, Jun Han, David R Goodlett, Davinder S Jassal, Ashish Shah, Amir Ravandi","doi":"10.1016/j.jlr.2025.100830","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100830","url":null,"abstract":"Introduction: Calcific aortic valve stenosis (CAVS) is a disease associated with significant morbidity and mortality in the aging population. Recently, bile acids have been shown to play a significant role in many disease processes, and untargeted metabolomic analyses of CAVS patient valves has shown a disrupted bile acid pathway.Aim: We aimed to understand the changes in human valvular bile acids in relation to CAVS severity.Methods: A total of 100 human aortic valves were collected from patients undergoing aortic valve replacement surgery. Bile acids were quantified by ultrahigh performance liquid chromatography coupled to tandem mass spectrometry.Results: Patients with mild aortic stenosis (AS) showed a distinct valvular bile acid composition compared to moderate and severe AS groups, with five bile acids being significantly elevated in patients with moderate and severe AS. These included norcholic, nordeoxycholic, glycodeoxycholic, glycocholic and taurodeoxycholic acid. When classified by calcification score, five species were significantly different between mild and severe AS groups; four bile acids were similar when stratified based on AS severity. Using k means clustering we were able to distinguish valve severity by their bile acid composition. Grouping bile acids by conjugation and by primary versus secondary revealed that conjugated primary and secondary bile acids were significantly increased in stenotic valves compared to the mild AS group.Conclusion: Conjugated bile acids are significantly elevated in the valvular tissue of patients with severe calcific aortic stenosis. These findings suggest a potential link between liverand gut microbiome physiologyand bile acid pathways in contributing to the pathophysiology of valvular stenosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100830"},"PeriodicalIF":5.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

N-Aldehyde-Modified Phosphatidylethanolamines generated by lipid peroxidation are robust substrates of N-Acyl Phosphatidylethanolamine Phospholipase D. 脂质过氧化生成的n -醛修饰磷脂酰乙醇胺是n -酰基磷脂酰乙醇胺磷脂酶D的强大底物。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-05-21 DOI: 10.1016/j.jlr.2025.100831

Reza Fadaei, Annie C Bernstein, Andrew N Jenkins, Allison G Pickens, Jonah E Zarrow, Abdul-Musawwir Alli-Oluwafuyi, Keri A Tallman, Sean S Davies

{"title":"N-Aldehyde-Modified Phosphatidylethanolamines generated by lipid peroxidation are robust substrates of N-Acyl Phosphatidylethanolamine Phospholipase D.","authors":"Reza Fadaei, Annie C Bernstein, Andrew N Jenkins, Allison G Pickens, Jonah E Zarrow, Abdul-Musawwir Alli-Oluwafuyi, Keri A Tallman, Sean S Davies","doi":"10.1016/j.jlr.2025.100831","DOIUrl":"10.1016/j.jlr.2025.100831","url":null,"abstract":"N-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) hydrolyzes phosphatidylethanolamines (PE) where the headgroup nitrogen has been enzymatically modified with acyl chains of four carbons or longer (N-acyl-PEs or NAPEs). The nitrogen headgroup of PE can also be non-enzymatically modified by reactive lipid aldehydes, thus forming N-aldehyde modified-PEs (NALPEs). Some NALPEs such as N-carboxyacyl-PEs are linked to PE via amide bonds similar to NAPEs, but others are linked by imine, pyrrole, or lactam moieties. Whether NAPE-PLD can hydrolyze NALPEs was unknown. We therefore characterized the major NALPE species formed during lipid peroxidation of arachidonic acid and linoleic acid and generated various NALPEs for characterization of their sensitivity to NAPE-PLD hydrolysis by reacting synthesized aldehydes with PE. We found that NAPE-PLD could act on NALPEs of various lengths and linkage types including those derived from PE modified by malondialdehyde (N-MDA-PE), 4-hydroxynonenal (N-HNE-PE), 4-oxo-nonenal (N-ONE-PE), 9-keto-12-oxo-dodecenoic acid (N-KODA-PE), and 15-E2-isolevuglandin (N-IsoLG-PE). To assess the relative preference of NAPE-PLD for various NALPEs versus its canonical NAPE substrates, we generated a substrate mixture containing roughly equimolar concentrations of seven NALPEs as well as two NAPEs (N-palmitoyl-PE and N-linoleoyl-PE) and measured their rate of hydrolysis. Several NALPE species, including the N-HNE-PE pyrrole species, were hydrolyzed at a similar rate as N-linoleoyl-PE and many of the other NALPEs showed intermediate rates of hydrolysis. These results significantly expand the substrate repertoire of NAPE-PLD and suggest that it may play an important role in clearing products of lipid peroxidation in addition to its established role in the biosynthesis of N-acyl-ethanolamines.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100831"},"PeriodicalIF":5.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0