Pub Date : 2025-01-01Epub Date: 2024-11-19DOI: 10.1016/j.jlr.2024.100700
Victoria A Ismail, Meg Schuetz, Zak N Baker, Jean A Castillo-Badillo, Teri V Naismith, David J Pagliarini, David J Kast
Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.
{"title":"DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis.","authors":"Victoria A Ismail, Meg Schuetz, Zak N Baker, Jean A Castillo-Badillo, Teri V Naismith, David J Pagliarini, David J Kast","doi":"10.1016/j.jlr.2024.100700","DOIUrl":"10.1016/j.jlr.2024.100700","url":null,"abstract":"<p><p>Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100700"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-19DOI: 10.1016/j.jlr.2024.100706
Kathryn M Spitler, Shwetha K Shetty, Brandon S J Davies
Both age and diet can contribute to alterations in triglyceride metabolism and subsequent metabolic disease. In humans, plasma triglyceride levels increase with age. Diets high in saturated fats can increase triglyceride levels while diets high in omega-3 fatty acids decrease triglyceride levels. Here we asked how age and long-term diet altered triglyceride metabolism in mice. We fed male and female C57Bl/6 mice a low-fat diet, a western diet (WD), or a diet high in polyunsaturated and omega-3 fatty acids (n3D) for up to 2 years. We measured survival, body composition, plasma triglyceride levels, chylomicron clearance, and oral fat, glucose, and insulin tolerance. Triglyceride levels in mice did not increase with age, regardless of diet. Oral fat tolerance increased with age, while chylomicron clearance remained unchanged. Decreased survival was observed in WD-fed mice. Interestingly, n3D-fed mice gained more lean mass and had lower insulin levels than WD-fed or LFD-fed mice. Moreover, triglyceride uptake into the hearts of n3D-fed mice was strikingly higher than in other groups. Our data indicate that in C57Bl/6 mice, age-induced changes in triglyceride metabolism differ from those observed in humans. Mice, like humans, appeared to have decreased fat absorption with age, but in mice plasma triglyceride clearance did not decrease with age, resulting in lower plasma triglyceride levels and improved fat tolerance with age. Although a chronic diet high in omega-3 fatty acids increased insulin sensitivity and triglyceride uptake specifically into the heart, how these observations are connected is unclear.
{"title":"Effects of age and diet on triglyceride metabolism in mice.","authors":"Kathryn M Spitler, Shwetha K Shetty, Brandon S J Davies","doi":"10.1016/j.jlr.2024.100706","DOIUrl":"10.1016/j.jlr.2024.100706","url":null,"abstract":"<p><p>Both age and diet can contribute to alterations in triglyceride metabolism and subsequent metabolic disease. In humans, plasma triglyceride levels increase with age. Diets high in saturated fats can increase triglyceride levels while diets high in omega-3 fatty acids decrease triglyceride levels. Here we asked how age and long-term diet altered triglyceride metabolism in mice. We fed male and female C57Bl/6 mice a low-fat diet, a western diet (WD), or a diet high in polyunsaturated and omega-3 fatty acids (n3D) for up to 2 years. We measured survival, body composition, plasma triglyceride levels, chylomicron clearance, and oral fat, glucose, and insulin tolerance. Triglyceride levels in mice did not increase with age, regardless of diet. Oral fat tolerance increased with age, while chylomicron clearance remained unchanged. Decreased survival was observed in WD-fed mice. Interestingly, n3D-fed mice gained more lean mass and had lower insulin levels than WD-fed or LFD-fed mice. Moreover, triglyceride uptake into the hearts of n3D-fed mice was strikingly higher than in other groups. Our data indicate that in C57Bl/6 mice, age-induced changes in triglyceride metabolism differ from those observed in humans. Mice, like humans, appeared to have decreased fat absorption with age, but in mice plasma triglyceride clearance did not decrease with age, resulting in lower plasma triglyceride levels and improved fat tolerance with age. Although a chronic diet high in omega-3 fatty acids increased insulin sensitivity and triglyceride uptake specifically into the heart, how these observations are connected is unclear.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100706"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-22DOI: 10.1016/j.jlr.2024.100713
Guiwen Xu, Wei Xiao, Pengqi Sun, Yuanjun Sun, Xinyu Yang, Xiaomeng Yin, Yang Liu
Diastolic dysfunction in aging mice is linked to mitochondrial abnormalities, including mitochondrial morphology disorders and decreases in membrane potential. Studies also show that aberrant mitochondrial lipid metabolism impairs mitochondrial function in aging cardiomyocytes. Our lipidomic analysis revealed that phosphatidylethanolamine (PE) levels were significantly decreased in aging myocardial mitochondria. Here, we investigated whether a reduction in PE levels in myocardial mitochondria contributes to mitochondrial injury as well as HFpEF pathogenesis and whether modulation of PE levels could ameliorate aging-induced HFpEF. Echocardiography was used to assess cardiac diastolic function in adult and aging mice treated with lysophosphatidylethanolamine (LPE) or saline. Mitochondrial morphologies from tissue samples were evaluated by transmission electron microscopy (TEM), while mitochondrial membrane potential and reactive oxygen species (ROS) levels were assessed using JC-1, MitoSOX, and DCFH-DA detection assays. We performed GO enrichment analysis between adult and aging mice and discovered significant enrichment in transcriptional programs associated with mitochondria and lipid metabolism. Also, mitochondrial PE levels were significantly decreased in aging cardiomyocytes. Treatment with LPE (200 μg/kg) significantly enhanced PE content in aging mice and improved the structure of mitochondria in cardiac cells. Also, LPE treatment protects against aging-induced deterioration of mitochondrial injury, as evidenced by increased mitochondrial membrane potential and decreased mitochondrial ROS. Furthermore, treatment with LPE alleviated severe diastolic dysfunction in aging mice. Taken together, our results suggest that LPE treatment enhances PE levels in mitochondria and ameliorates aging-induced diastolic dysfunction in mice through a mechanism involving improved mitochondrial structure and function.
衰老小鼠的舒张功能障碍与线粒体异常有关,包括线粒体形态紊乱和膜电位下降。研究还表明,线粒体脂质代谢异常会损害衰老心肌细胞的线粒体功能。我们的脂质体分析表明,衰老心肌线粒体中磷脂酰乙醇胺(PE)的水平显著下降。在此,我们研究了心肌线粒体中 PE 水平的降低是否会导致线粒体损伤以及 HFpEF 的发病机制,以及调节 PE 水平是否能改善衰老诱导的 HFpEF。用超声心动图评估成年小鼠和老龄小鼠接受溶血磷脂酰乙醇胺(LPE)或生理盐水治疗后的心脏舒张功能。组织样本的线粒体形态由透射电子显微镜(TEM)进行评估,线粒体膜电位和活性氧(ROS)水平则由JC-1、MitoSOX和DCFH-DA检测法进行评估。我们对成年小鼠和衰老小鼠进行了GO富集分析,发现与线粒体和脂质代谢相关的转录程序显著富集。此外,在衰老的心肌细胞中,线粒体 PE 含量明显下降。用 LPE 治疗可明显提高衰老小鼠的 PE 含量,并改善心肌细胞线粒体的结构。此外,LPE 治疗还能防止衰老引起的线粒体损伤恶化,线粒体膜电位的增加和线粒体 ROS 的减少都证明了这一点。此外,LPE 还能缓解衰老小鼠严重的舒张功能障碍。综上所述,我们的研究结果表明,LPE 治疗可提高线粒体中的 PE 水平,并通过改善线粒体结构和功能的机制来改善衰老引起的小鼠舒张功能障碍。
{"title":"Lysophosphatidylethanolamine improves diastolic dysfunction by alleviating mitochondrial injury in the aging heart.","authors":"Guiwen Xu, Wei Xiao, Pengqi Sun, Yuanjun Sun, Xinyu Yang, Xiaomeng Yin, Yang Liu","doi":"10.1016/j.jlr.2024.100713","DOIUrl":"10.1016/j.jlr.2024.100713","url":null,"abstract":"<p><p>Diastolic dysfunction in aging mice is linked to mitochondrial abnormalities, including mitochondrial morphology disorders and decreases in membrane potential. Studies also show that aberrant mitochondrial lipid metabolism impairs mitochondrial function in aging cardiomyocytes. Our lipidomic analysis revealed that phosphatidylethanolamine (PE) levels were significantly decreased in aging myocardial mitochondria. Here, we investigated whether a reduction in PE levels in myocardial mitochondria contributes to mitochondrial injury as well as HFpEF pathogenesis and whether modulation of PE levels could ameliorate aging-induced HFpEF. Echocardiography was used to assess cardiac diastolic function in adult and aging mice treated with lysophosphatidylethanolamine (LPE) or saline. Mitochondrial morphologies from tissue samples were evaluated by transmission electron microscopy (TEM), while mitochondrial membrane potential and reactive oxygen species (ROS) levels were assessed using JC-1, MitoSOX, and DCFH-DA detection assays. We performed GO enrichment analysis between adult and aging mice and discovered significant enrichment in transcriptional programs associated with mitochondria and lipid metabolism. Also, mitochondrial PE levels were significantly decreased in aging cardiomyocytes. Treatment with LPE (200 μg/kg) significantly enhanced PE content in aging mice and improved the structure of mitochondria in cardiac cells. Also, LPE treatment protects against aging-induced deterioration of mitochondrial injury, as evidenced by increased mitochondrial membrane potential and decreased mitochondrial ROS. Furthermore, treatment with LPE alleviated severe diastolic dysfunction in aging mice. Taken together, our results suggest that LPE treatment enhances PE levels in mitochondria and ameliorates aging-induced diastolic dysfunction in mice through a mechanism involving improved mitochondrial structure and function.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100713"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-20DOI: 10.1016/j.jlr.2024.100710
Ujjalkumar S Das, Garret A FitzGerald
{"title":"Chiral clues to lipid identity.","authors":"Ujjalkumar S Das, Garret A FitzGerald","doi":"10.1016/j.jlr.2024.100710","DOIUrl":"10.1016/j.jlr.2024.100710","url":null,"abstract":"","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100710"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-02DOI: 10.1016/j.jlr.2024.100719
Anne G Ostermeyer-Fay, Abhay Kanodia, Ranjana Pathak, Maria Jose Hernandez-Corbacho, Aarnoud C van der Spoel, Yusuf A Hannun, Daniel Canals
During the last 30 years, an increasing number of cellular functions have been reported to be regulated by the lipid ceramide. The diversity in the ceramide structure, leading to tens of ceramide species and the discrete distribution based on subcellular topology, could explain the wide variety of functions attributed to this bioactive lipid. One of these pools of ceramide resides in the plasma membrane, and several works have suggested that an increase in plasma membrane ceramide (PMCer) in response to stimulation leads to cell death and modulates cell adhesion and migration. However, there is a limitation in studying PMCer content in this location primarily due to the inability to quantify its mass. Our group recently developed a method to specifically quantitate PMCer. In this work, we interrogate what sphingolipid metabolizing enzymes are responsible for modulating the basal levels of plasma membrane ceramide. An in-silico prediction and experimental confirmation found an almost perfect correlation between the endogenous expression levels of neutral sphingomyelinase (nSMase2) and the amount of plasma membrane ceramide in unstimulated cells. Manipulating the expression levels of nSMase2, but not other candidate enzymes of ceramide metabolism, profoundly affected PMCer. Moreover, a physiologic induction of nSMase2 during cell confluence resulted in a nSMase2-dependent dramatic increase in PMCer. Together, these results identify nSMase2 as the primary enzyme to regulate plasma membrane ceramide.
{"title":"The steady-state level of plasma membrane ceramide is regulated by neutral sphingomyelinase 2.","authors":"Anne G Ostermeyer-Fay, Abhay Kanodia, Ranjana Pathak, Maria Jose Hernandez-Corbacho, Aarnoud C van der Spoel, Yusuf A Hannun, Daniel Canals","doi":"10.1016/j.jlr.2024.100719","DOIUrl":"10.1016/j.jlr.2024.100719","url":null,"abstract":"<p><p>During the last 30 years, an increasing number of cellular functions have been reported to be regulated by the lipid ceramide. The diversity in the ceramide structure, leading to tens of ceramide species and the discrete distribution based on subcellular topology, could explain the wide variety of functions attributed to this bioactive lipid. One of these pools of ceramide resides in the plasma membrane, and several works have suggested that an increase in plasma membrane ceramide (PMCer) in response to stimulation leads to cell death and modulates cell adhesion and migration. However, there is a limitation in studying PMCer content in this location primarily due to the inability to quantify its mass. Our group recently developed a method to specifically quantitate PMCer. In this work, we interrogate what sphingolipid metabolizing enzymes are responsible for modulating the basal levels of plasma membrane ceramide. An in-silico prediction and experimental confirmation found an almost perfect correlation between the endogenous expression levels of neutral sphingomyelinase (nSMase2) and the amount of plasma membrane ceramide in unstimulated cells. Manipulating the expression levels of nSMase2, but not other candidate enzymes of ceramide metabolism, profoundly affected PMCer. Moreover, a physiologic induction of nSMase2 during cell confluence resulted in a nSMase2-dependent dramatic increase in PMCer. Together, these results identify nSMase2 as the primary enzyme to regulate plasma membrane ceramide.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100719"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-17DOI: 10.1016/j.jlr.2024.100697
Martin Roumain, Giulio G Muccioli
Oxysterols and bile acids are interconnected bioactive lipids playing pivotal roles in diverse physiological and pathological processes. For this reason, they are increasingly studied together for their implications in various diseases. However, due to analytical challenges inherent to the nature of these analytes, very few methods have been developed for the simultaneous analysis of these lipids. We here report the development of a sensitive LC-MS/MS method for the combined quantification of 18 oxysterols, 11 unconjugated, 15 conjugated bile acids, and 1 bile acid precursor, using 8 isotope-labeled internal standards, addressing the need for a more comprehensive analysis of these interesting lipid families. During the method development, we investigated different extraction protocols, set up a purification step, and achieved chromatographic separation for these lipids, overcoming challenges such as the large number of analytes, isomers, and wide range of polarity across the analytes. Finally, the method was successfully applied to the analysis of preclinical and clinical samples, quantifying 12 oxysterols and 14 bile acids in human plasma, 10 oxysterols and 18 bile acids in mouse plasma from the vena cava, and 10 oxysterols and 20 bile acids in mouse plasma from the portal vein within a single chromatographic run.
{"title":"Development and application of an LC-MS/MS method for the combined quantification of oxysterols and bile acids.","authors":"Martin Roumain, Giulio G Muccioli","doi":"10.1016/j.jlr.2024.100697","DOIUrl":"10.1016/j.jlr.2024.100697","url":null,"abstract":"<p><p>Oxysterols and bile acids are interconnected bioactive lipids playing pivotal roles in diverse physiological and pathological processes. For this reason, they are increasingly studied together for their implications in various diseases. However, due to analytical challenges inherent to the nature of these analytes, very few methods have been developed for the simultaneous analysis of these lipids. We here report the development of a sensitive LC-MS/MS method for the combined quantification of 18 oxysterols, 11 unconjugated, 15 conjugated bile acids, and 1 bile acid precursor, using 8 isotope-labeled internal standards, addressing the need for a more comprehensive analysis of these interesting lipid families. During the method development, we investigated different extraction protocols, set up a purification step, and achieved chromatographic separation for these lipids, overcoming challenges such as the large number of analytes, isomers, and wide range of polarity across the analytes. Finally, the method was successfully applied to the analysis of preclinical and clinical samples, quantifying 12 oxysterols and 14 bile acids in human plasma, 10 oxysterols and 18 bile acids in mouse plasma from the vena cava, and 10 oxysterols and 20 bile acids in mouse plasma from the portal vein within a single chromatographic run.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100697"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-21DOI: 10.1016/j.jlr.2024.100712
Vera F Monteiro-Cardoso, Xin Yi Yeo, Han-Gyu Bae, David Castano Mayan, Mariam Wehbe, Sejin Lee, Kumar Krishna-K, Seung Hyun Baek, Leon F Palomera, Lik Hang Wu, Leroy S Pakkiri, Sangeetha Shanmugam, Kai Ping Sem, Mun Geok Yew, Matthew P Parsons, Michael R Hayden, Leonard L L Yeo, Vijay K Sharma, Chester Drum, Elisa A Liehn, Sreedharan Sajikumar, Svend Davanger, Dong-Gyu Jo, Mark Y Y Chan, Benjamin Y Q Tan, Sangyong Jung, Roshni R Singaraja
Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1-/-, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1-/- and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1-/- brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1-/- mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.
{"title":"The bile acid chenodeoxycholic acid associates with reduced stroke in humans and mice.","authors":"Vera F Monteiro-Cardoso, Xin Yi Yeo, Han-Gyu Bae, David Castano Mayan, Mariam Wehbe, Sejin Lee, Kumar Krishna-K, Seung Hyun Baek, Leon F Palomera, Lik Hang Wu, Leroy S Pakkiri, Sangeetha Shanmugam, Kai Ping Sem, Mun Geok Yew, Matthew P Parsons, Michael R Hayden, Leonard L L Yeo, Vijay K Sharma, Chester Drum, Elisa A Liehn, Sreedharan Sajikumar, Svend Davanger, Dong-Gyu Jo, Mark Y Y Chan, Benjamin Y Q Tan, Sangyong Jung, Roshni R Singaraja","doi":"10.1016/j.jlr.2024.100712","DOIUrl":"10.1016/j.jlr.2024.100712","url":null,"abstract":"<p><p>Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1<sup>-/-</sup>, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1<sup>-/-</sup> and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1<sup>-/-</sup> brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1<sup>-/-</sup> mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100712"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-03DOI: 10.1016/j.jlr.2024.100718
Yu Fu, Xin Hao, Jingru Nie, Peng Shang, Xinxing Dong, Bo Zhang, Dawei Yan, Hao Zhang
Adipose tissue, an important organ involved in energy metabolism and endocrine, is closely related to animal meat quality and human health. Transient receptor potential channel 1 (TRPC1), an ion transporter, is adipocytes' major Ca2+ entry channel. However, its function in fat deposition is poorly understood, particularly in pigs, which are both an ideal model for human obesity research and a primary meat source for human diets. In the present investigation, our findings demonstrate a prominent expression of TRPC1 within the adipose tissue of pigs with a strong fat deposition ability. Functional analysis showed that TRPC1 promotes primary preadipocyte proliferation and adipogenic differentiation. In vivo, transgenic mice expressing porcine TRPC1 exhibited aggravated high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, TRPC1 may facilitate adipogenesis via activating phosphatidylinositol 3 kinase/AKT and β-catenin signaling pathways. Our research underscores the pivotal role of porcine TRPC1 as a positive regulator in adipogenesis and lipid accumulation processes, providing a potential target for improving animal meat quality and treating obesity-related diseases in humans.
{"title":"Porcine transient receptor potential channel 1 promotes adipogenesis and lipid deposition.","authors":"Yu Fu, Xin Hao, Jingru Nie, Peng Shang, Xinxing Dong, Bo Zhang, Dawei Yan, Hao Zhang","doi":"10.1016/j.jlr.2024.100718","DOIUrl":"10.1016/j.jlr.2024.100718","url":null,"abstract":"<p><p>Adipose tissue, an important organ involved in energy metabolism and endocrine, is closely related to animal meat quality and human health. Transient receptor potential channel 1 (TRPC1), an ion transporter, is adipocytes' major Ca<sup>2+</sup> entry channel. However, its function in fat deposition is poorly understood, particularly in pigs, which are both an ideal model for human obesity research and a primary meat source for human diets. In the present investigation, our findings demonstrate a prominent expression of TRPC1 within the adipose tissue of pigs with a strong fat deposition ability. Functional analysis showed that TRPC1 promotes primary preadipocyte proliferation and adipogenic differentiation. In vivo, transgenic mice expressing porcine TRPC1 exhibited aggravated high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, TRPC1 may facilitate adipogenesis via activating phosphatidylinositol 3 kinase/AKT and β-catenin signaling pathways. Our research underscores the pivotal role of porcine TRPC1 as a positive regulator in adipogenesis and lipid accumulation processes, providing a potential target for improving animal meat quality and treating obesity-related diseases in humans.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100718"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-05DOI: 10.1016/j.jlr.2024.100720
Yibing Lv, Yidan Zheng, Shanshan Su, Junyi Xiao, Jie Yang, Lingyun Xiong, Yanyan Guo, Xiaoqi Zhou, Nengqiang Guo, Ping Lei
The role of the monocyte marker CD14 in the regulation of obesity is increasingly recognized. Our observations indicated that Cd14-/- mice exhibited a leaner body shape compared to their wild-type (WT) counterparts. And the loss of CD14 alleviated high-fat diet-induced obesity in mice. In human subjects, CD14 level was tested to be positively correlated with overweight and obesity. However, the relationship between CD14 and the development of obesity remains only partially understood. To investigate the underlying mechanisms, adipose tissues (ATs) from Cd14-/- and WT mice were subjected to deep RNA sequencing. Gene Ontology enrichment analysis revealed a significant enhancement of angiogenesis-related function in the Cd14-/- epididymal adipose tissues compared to WT counterpart, which was accompanied by an upregulation of Cd301b. Subsequent assays confirmed the enhanced angiogenesis and more accumulation of CD301b+ macrophages in Cd14-/- epididymal adipose tissues. Because Igf1 expression has been suggested to be associated with Cd301b expression through pseudotime analysis, we found it was insulin-like growth factor 1 secreted from Cd14-/- macrophages that mediated the angiogenesis enhancement. Collectively, our findings indicate that CD14 deficiency increased the accumulation of CD14loCD301b+ macrophages in ATs, which may serve as a proangiogenic marker, providing novel insights into the relationship between CD14 and obesity development.
{"title":"CD14<sup>lo</sup>CD301b<sup>+</sup> macrophages gathering as a proangiogenic marker in adipose tissues.","authors":"Yibing Lv, Yidan Zheng, Shanshan Su, Junyi Xiao, Jie Yang, Lingyun Xiong, Yanyan Guo, Xiaoqi Zhou, Nengqiang Guo, Ping Lei","doi":"10.1016/j.jlr.2024.100720","DOIUrl":"10.1016/j.jlr.2024.100720","url":null,"abstract":"<p><p>The role of the monocyte marker CD14 in the regulation of obesity is increasingly recognized. Our observations indicated that Cd14<sup>-/-</sup> mice exhibited a leaner body shape compared to their wild-type (WT) counterparts. And the loss of CD14 alleviated high-fat diet-induced obesity in mice. In human subjects, CD14 level was tested to be positively correlated with overweight and obesity. However, the relationship between CD14 and the development of obesity remains only partially understood. To investigate the underlying mechanisms, adipose tissues (ATs) from Cd14<sup>-/-</sup> and WT mice were subjected to deep RNA sequencing. Gene Ontology enrichment analysis revealed a significant enhancement of angiogenesis-related function in the Cd14<sup>-/-</sup> epididymal adipose tissues compared to WT counterpart, which was accompanied by an upregulation of Cd301b. Subsequent assays confirmed the enhanced angiogenesis and more accumulation of CD301b<sup>+</sup> macrophages in Cd14<sup>-/-</sup> epididymal adipose tissues. Because Igf1 expression has been suggested to be associated with Cd301b expression through pseudotime analysis, we found it was insulin-like growth factor 1 secreted from Cd14<sup>-/-</sup> macrophages that mediated the angiogenesis enhancement. Collectively, our findings indicate that CD14 deficiency increased the accumulation of CD14<sup>lo</sup>CD301b<sup>+</sup> macrophages in ATs, which may serve as a proangiogenic marker, providing novel insights into the relationship between CD14 and obesity development.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100720"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-14DOI: 10.1016/j.jlr.2024.100730
Shelley Barnhart, Masami Shimizu-Albergine, Eyal Kedar, Vishal Kothari, Baohai Shao, Melissa Krueger, Cheng-Chieh Hsu, Jingjing Tang, Jenny E Kanter, Farah Kramer, Danijel Djukovic, Vadim Pascua, Yueh-Ming Loo, Lucrezia Colonna, Sadie J Van den Bogaerde, Jie An, Michael Gale, Karen Reue, Edward A Fisher, Sina A Gharib, Keith B Elkon, Karin E Bornfeldt
Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.
{"title":"Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.","authors":"Shelley Barnhart, Masami Shimizu-Albergine, Eyal Kedar, Vishal Kothari, Baohai Shao, Melissa Krueger, Cheng-Chieh Hsu, Jingjing Tang, Jenny E Kanter, Farah Kramer, Danijel Djukovic, Vadim Pascua, Yueh-Ming Loo, Lucrezia Colonna, Sadie J Van den Bogaerde, Jie An, Michael Gale, Karen Reue, Edward A Fisher, Sina A Gharib, Keith B Elkon, Karin E Bornfeldt","doi":"10.1016/j.jlr.2024.100730","DOIUrl":"10.1016/j.jlr.2024.100730","url":null,"abstract":"<p><p>Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100730"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}