Pub Date : 2025-03-17DOI: 10.1016/j.metabol.2025.156195
Gonzalo Fernández-Duval, Cristina Razquin, Fenglei Wang, Huan Yun, Jie Hu, Marta Guasch-Ferré, Kathryn Rexrode, Raji Balasubramanian, Jesús García-Gavilán, Miguel Ruiz-Canela, Clary B Clish, Dolores Corella, Enrique Gómez-Gracia, Miquel Fiol, Ramón Estruch, José Lapetra, Montse Fitó, Luis Serra-Majem, Emilio Ros, Liming Liang, Courtney Dennis, Eva M Asensio, Olga Castañer, Francisco J Planes, Jordi Salas-Salvadó, Frank B Hu, Estefanía Toledo, Miguel A Martínez-González
Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseline plasma metabolites repeatedly assessed at baseline and after 1 year, 38 plasma metabolites were identified as predictors of all-cause mortality. Gamma-amino-butyric acid (GABA), homoarginine, serine, creatine, 1-methylnicotinamide and a set of sphingomyelins, plasmalogens, phosphatidylethanolamines and cholesterol esters were inversely associated with all-cause mortality, whereas plasma dimethylguanidino valeric acid (DMGV), choline, short and long-chain acylcarnitines, 4-acetamidobutanoate, pseudouridine, 7-methylguanine, N6-acetyllysine, phenylacetylglutamine and creatinine were associated with higher mortality. The multi-metabolite signature created as a linear combination of these selected metabolites, also showed a strong association with all-cause mortality using plasma samples collected at 1-year follow-up in PREDIMED. This association was subsequently confirmed in 4 independent American cohorts, validating the signature as a consistent predictor of all-cause mortality across diverse populations.
{"title":"A multi-metabolite signature robustly predicts long-term mortality in the PREDIMED trial and several US cohorts.","authors":"Gonzalo Fernández-Duval, Cristina Razquin, Fenglei Wang, Huan Yun, Jie Hu, Marta Guasch-Ferré, Kathryn Rexrode, Raji Balasubramanian, Jesús García-Gavilán, Miguel Ruiz-Canela, Clary B Clish, Dolores Corella, Enrique Gómez-Gracia, Miquel Fiol, Ramón Estruch, José Lapetra, Montse Fitó, Luis Serra-Majem, Emilio Ros, Liming Liang, Courtney Dennis, Eva M Asensio, Olga Castañer, Francisco J Planes, Jordi Salas-Salvadó, Frank B Hu, Estefanía Toledo, Miguel A Martínez-González","doi":"10.1016/j.metabol.2025.156195","DOIUrl":"10.1016/j.metabol.2025.156195","url":null,"abstract":"<p><p>Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseline plasma metabolites repeatedly assessed at baseline and after 1 year, 38 plasma metabolites were identified as predictors of all-cause mortality. Gamma-amino-butyric acid (GABA), homoarginine, serine, creatine, 1-methylnicotinamide and a set of sphingomyelins, plasmalogens, phosphatidylethanolamines and cholesterol esters were inversely associated with all-cause mortality, whereas plasma dimethylguanidino valeric acid (DMGV), choline, short and long-chain acylcarnitines, 4-acetamidobutanoate, pseudouridine, 7-methylguanine, N6-acetyllysine, phenylacetylglutamine and creatinine were associated with higher mortality. The multi-metabolite signature created as a linear combination of these selected metabolites, also showed a strong association with all-cause mortality using plasma samples collected at 1-year follow-up in PREDIMED. This association was subsequently confirmed in 4 independent American cohorts, validating the signature as a consistent predictor of all-cause mortality across diverse populations.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156195"},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-15DOI: 10.1016/j.metabol.2025.156191
Leon G. Straub , Jan-Bernd Funcke , Nolwenn Joffin , Chanmin Joung , Sara Al-Ghadban , Shangang Zhao , Qingzhang Zhu , Ilja L. Kruglikov , Yi Zhu , Paul R. Langlais , Ruth Gordillo , Karen L. Herbst , Philipp E. Scherer
Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (ClinicalTrial.gov, NCT02838277), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, PXD058489) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.
{"title":"Defining lipedema's molecular hallmarks by multi-omics approach for disease prediction in women","authors":"Leon G. Straub , Jan-Bernd Funcke , Nolwenn Joffin , Chanmin Joung , Sara Al-Ghadban , Shangang Zhao , Qingzhang Zhu , Ilja L. Kruglikov , Yi Zhu , Paul R. Langlais , Ruth Gordillo , Karen L. Herbst , Philipp E. Scherer","doi":"10.1016/j.metabol.2025.156191","DOIUrl":"10.1016/j.metabol.2025.156191","url":null,"abstract":"<div><div>Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (<span><span>ClinicalTrial.gov</span><svg><path></path></svg></span>, <span><span>NCT02838277</span><svg><path></path></svg></span>), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, <span><span>PXD058489</span><svg><path></path></svg></span>) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156191"},"PeriodicalIF":10.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-11DOI: 10.1016/j.metabol.2025.156190
Xinrong Zhang , Mindie H. Nguyen
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.
{"title":"Metabolic dysfunction-associated steatotic liver disease: A sexually dimorphic disease and breast and gynecological cancer","authors":"Xinrong Zhang , Mindie H. Nguyen","doi":"10.1016/j.metabol.2025.156190","DOIUrl":"10.1016/j.metabol.2025.156190","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156190"},"PeriodicalIF":10.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-11DOI: 10.1016/j.metabol.2025.156188
Getachew Arage , Koen F. Dekkers , Luka Marko Rašo , Ulf Hammar , Ulrika Ericson , Susanna C. Larsson , Hanna Engel , Gabriel Baldanzi , Kamalita Pertiwi , Sergi Sayols-Baixeras , Rikard Landberg , Johan Sundström , J. Gustav Smith , Gunnar Engström , Johan Ärnlöv , Marju Orho-Melander , Lars Lind , Tove Fall , Shafqat Ahmad
Background
Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with cardiometabolic biomarkers, subclinical CVD markers, and incident CVD.
Methods
Associations between self-reported meat intake and 1272 plasma metabolites were investigated in the SCAPIS cohort (n = 8,819; ages 50–64). Meat-associated metabolites were further examined for relation with subclinical CVD markers in the POEM cohort (n = 502; age 50) and incident CVD in the EpiHealth cohort (n = 2,278; ages 45–75; 107 incident cases over 9.6 years follow-up). Meat intake was categorized into white, unprocessed red, and processed red meat. Linear regression analyzed associations between meat intake, metabolites and cardiometabolic biomarkers, and subclinical CVD markers, while Cox models evaluated association between meat-associated metabolites and incident CVD.
Results
After correction for multiple testing, 458, 368, and 403 metabolites were associated with white, unprocessed red, and processed red meat, respectively. Processed red meat-associated metabolites were associated with higher levels of fasting insulin, hemoglobin A1c, and lipoprotein(a), and were inversely associated with maximal oxygen consumption. Two metabolites, 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (hazard ratios (HR: 1.32; 95 % CI: 1.08, 1.62)) and glutamine degradant (HR: 1.35; 95 % CI: 1.07, 1.72), that were inversely associated with intake of all meat types, were also associated with a higher risk of incident CVD.
Conclusions
This study provides comprehensive analysis of self-reported meat intake and plasma metabolites. The findings may enhance our understanding of the relationship between meat intake and CVD, and provide insights into underlying mechanisms.
{"title":"Plasma metabolite profiles of meat intake and their association with cardiovascular disease risk: A population-based study in Swedish cohorts","authors":"Getachew Arage , Koen F. Dekkers , Luka Marko Rašo , Ulf Hammar , Ulrika Ericson , Susanna C. Larsson , Hanna Engel , Gabriel Baldanzi , Kamalita Pertiwi , Sergi Sayols-Baixeras , Rikard Landberg , Johan Sundström , J. Gustav Smith , Gunnar Engström , Johan Ärnlöv , Marju Orho-Melander , Lars Lind , Tove Fall , Shafqat Ahmad","doi":"10.1016/j.metabol.2025.156188","DOIUrl":"10.1016/j.metabol.2025.156188","url":null,"abstract":"<div><h3>Background</h3><div>Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with cardiometabolic biomarkers, subclinical CVD markers, and incident CVD.</div></div><div><h3>Methods</h3><div>Associations between self-reported meat intake and 1272 plasma metabolites were investigated in the SCAPIS cohort (<em>n</em> = 8,819; ages 50–64). Meat-associated metabolites were further examined for relation with subclinical CVD markers in the POEM cohort (<em>n</em> = 502; age 50) and incident CVD in the EpiHealth cohort (<em>n</em> = 2,278; ages 45–75; 107 incident cases over 9.6 years follow-up). Meat intake was categorized into white, unprocessed red, and processed red meat. Linear regression analyzed associations between meat intake, metabolites and cardiometabolic biomarkers, and subclinical CVD markers, while Cox models evaluated association between meat-associated metabolites and incident CVD.</div></div><div><h3>Results</h3><div>After correction for multiple testing, 458, 368, and 403 metabolites were associated with white, unprocessed red, and processed red meat, respectively. Processed red meat-associated metabolites were associated with higher levels of fasting insulin, hemoglobin A1c, and lipoprotein(a), and were inversely associated with maximal oxygen consumption. Two metabolites, 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (hazard ratios (HR: 1.32; 95 % CI: 1.08, 1.62)) and glutamine degradant (HR: 1.35; 95 % CI: 1.07, 1.72), that were inversely associated with intake of all meat types, were also associated with a higher risk of incident CVD.</div></div><div><h3>Conclusions</h3><div>This study provides comprehensive analysis of self-reported meat intake and plasma metabolites. The findings may enhance our understanding of the relationship between meat intake and CVD, and provide insights into underlying mechanisms.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156188"},"PeriodicalIF":10.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-11DOI: 10.1016/j.metabol.2025.156186
Chunmei Xiu , Lei Zhang , Chenxi Zhang , Yuannan Zhang , Xi Luo , Ziyi Zhang , Hangkai Zhao , Kaizhong Ji , Zhiyuan Chen , Guangxu He , Jianquan Chen
Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated de novo lipogenesis (DNL) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of DNL in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that Fasn expression and DNL levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by shRNA knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation in vitro. Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, i.e. ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.
{"title":"Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling","authors":"Chunmei Xiu , Lei Zhang , Chenxi Zhang , Yuannan Zhang , Xi Luo , Ziyi Zhang , Hangkai Zhao , Kaizhong Ji , Zhiyuan Chen , Guangxu He , Jianquan Chen","doi":"10.1016/j.metabol.2025.156186","DOIUrl":"10.1016/j.metabol.2025.156186","url":null,"abstract":"<div><div>Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated <em>de novo</em> lipogenesis (<em>DNL</em>) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of <em>DNL</em> in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that <em>Fasn</em> expression and <em>DNL</em> levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by <em>shRNA</em> knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation <em>in vitro</em>. Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, <em>i.e.</em> ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated <em>DNL</em> is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156186"},"PeriodicalIF":10.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-10DOI: 10.1016/j.metabol.2025.156189
Morten Hindsø , Annemarie Lundsgaard , Bojan Marinkovic , Mikkel Helmuth Jensen , Nora Hedbäck , Maria Saur Svane , Carsten Dirksen , Nils Bruun Jørgensen , Amalie London , Palle Bekker Jeppesen , Mark Krogh Hvistendahl , Christina Christoffersen , Hartwig Roman Siebner , Bente Kiens , Jens Juul Holst , Sten Madsbad , Gerrit van Hall , Kirstine Nyvold Bojsen-Møller
Background
Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI.
Methods
Participants followed a 7-day controlled diet and on day 4 underwent 1H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h.
Results
Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, P < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-h stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-h iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, P = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h.
Conclusion
Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.
背景：高脂肪餐后三酰甘油（TAG）血浆漂移在Roux-en-Y胃旁路（RYGB）后被减弱，但其潜在机制尚不清楚。我们研究了12例rygb手术个体和12例性别、年龄和BMI相匹配的未手术对照（CON）的TAG吸收和代谢。方法：参与者遵循7天的控制饮食，在第4天接受肝脏TAG的1H-MR光谱和高脂肪液体餐（含口服和静脉标记的稳定同位素代谢物），皮下腹部脂肪活检和间接量热法。随后，参与者收集粪便96 h。结果：RYGB组控制饮食的总脂肪吸收量略低于CON组（88 % vs 93 %,P ）。结论：RYGB组脂肪吸收量仅略低于未手术对照组。然而，高脂肪餐后的TAG和CM血浆动力学在RYGB后显著改变，TAG和CM-TAG浓度显著降低，尽管CM颗粒释放更快。
{"title":"Fat absorption and metabolism after Roux-en-Y gastric bypass surgery","authors":"Morten Hindsø , Annemarie Lundsgaard , Bojan Marinkovic , Mikkel Helmuth Jensen , Nora Hedbäck , Maria Saur Svane , Carsten Dirksen , Nils Bruun Jørgensen , Amalie London , Palle Bekker Jeppesen , Mark Krogh Hvistendahl , Christina Christoffersen , Hartwig Roman Siebner , Bente Kiens , Jens Juul Holst , Sten Madsbad , Gerrit van Hall , Kirstine Nyvold Bojsen-Møller","doi":"10.1016/j.metabol.2025.156189","DOIUrl":"10.1016/j.metabol.2025.156189","url":null,"abstract":"<div><h3>Background</h3><div>Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI.</div></div><div><h3>Methods</h3><div>Participants followed a 7-day controlled diet and on day 4 underwent <sup>1</sup>H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h.</div></div><div><h3>Results</h3><div>Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, <em>P</em> < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-h stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-h iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, <em>P</em> = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h.</div></div><div><h3>Conclusion</h3><div>Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156189"},"PeriodicalIF":10.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-10DOI: 10.1016/j.metabol.2025.156187
Mariana de Moura de Souza , Beatriz Ximenes Mendes , Maria Luiza Rodrigues Defante , Beatriz Austregélio de Athayde de Hollanda Morais , Otávio Cosendey Martins , Vitória Martins Prizão , Gabriela Romaniello
Introduction
Hypertriglyceridemia is related to atherosclerotic cardiovascular risk and pancreatitis risk. The efficacy and safety of apolipoprotein C-III (APOC-III) inhibitors remains unclear.
Aim
To investigate the effects of APOC-III inhibitors on hypertriglyceridemia and its complications.
Methods
We systematically searched PubMed, Embase, and Cochrane Central databases from inception to May 2024 for randomized controlled trials (RCTs) comparing APOC-III inhibitors to placebo in patients with hypertriglyceridemia. We pooled percentage standardized mean difference (SMD) changes and risk ratio (RR) for continuous and binary outcomes, respectively, with 95 % confidence interval (CI). Subgroup analyses were performed with APOC-III inhibitors drugs doses (Olezarsen, Volanesorsen and Plozasiran), and primary and secondary hypertriglyceridemia.
Results
10 RCTs with 1204 participants were included, of which 46 % were men. APOC-III inhibitors significantly reduced triglycerides (TG) (SMD: −60.56 %; 95 % CI −68.94 to −52.18; p < 0.00001), APOC-III (SMD: −75.44 %; 95 % CI −80.81 to −70.07; p < 0.00001) and non-HDL-c (SMD: −27.49 %; 95 % CI −34.16 to −20.82; p < 0.00001) levels. Consistent results were found for all subgroup analyses. APOC-III inhibitors were capable to normalize TG levels in patients with severe hypertriglyceridemia (RR: 7.92; 95 % CI 4.12 to 15.23; p < 0.00001). There was a significant increase in HDL-c (SMD: 43.92 %; 95 % CI 37.27 to 50.57; p < 0.00001) and LDL-c (SMD: 33.05 %; 95 % CI 9.08 to 57.01; p = 0.007) levels. There was a significant relative risk reduction in acute pancreatitis in the APOC-III inhibitors group (RR 0.17; 95 % CI 0.05 to 0.53; p = 0.007). Adverse events were similar in both groups.
Conclusion
APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia.
{"title":"Apolipoprotein C-III inhibitors for the treatment of hypertriglyceridemia: a meta-analysis of randomized controlled trials","authors":"Mariana de Moura de Souza , Beatriz Ximenes Mendes , Maria Luiza Rodrigues Defante , Beatriz Austregélio de Athayde de Hollanda Morais , Otávio Cosendey Martins , Vitória Martins Prizão , Gabriela Romaniello","doi":"10.1016/j.metabol.2025.156187","DOIUrl":"10.1016/j.metabol.2025.156187","url":null,"abstract":"<div><h3>Introduction</h3><div>Hypertriglyceridemia is related to atherosclerotic cardiovascular risk and pancreatitis risk. The efficacy and safety of apolipoprotein C-III (APOC-III) inhibitors remains unclear.</div></div><div><h3>Aim</h3><div>To investigate the effects of APOC-III inhibitors on hypertriglyceridemia and its complications.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed, Embase, and Cochrane Central databases from inception to May 2024 for randomized controlled trials (RCTs) comparing APOC-III inhibitors to placebo in patients with hypertriglyceridemia. We pooled percentage standardized mean difference (SMD) changes and risk ratio (RR) for continuous and binary outcomes, respectively, with 95 % confidence interval (CI). Subgroup analyses were performed with APOC-III inhibitors drugs doses (Olezarsen, Volanesorsen and Plozasiran), and primary and secondary hypertriglyceridemia.</div></div><div><h3>Results</h3><div>10 RCTs with 1204 participants were included, of which 46 % were men. APOC-III inhibitors significantly reduced triglycerides (TG) (SMD: −60.56 %; 95 % CI −68.94 to −52.18; p < 0.00001), APOC-III (SMD: −75.44 %; 95 % CI −80.81 to −70.07; p < 0.00001) and non-HDL-c (SMD: −27.49 %; 95 % CI −34.16 to −20.82; p < 0.00001) levels. Consistent results were found for all subgroup analyses. APOC-III inhibitors were capable to normalize TG levels in patients with severe hypertriglyceridemia (RR: 7.92; 95 % CI 4.12 to 15.23; p < 0.00001). There was a significant increase in HDL-c (SMD: 43.92 %; 95 % CI 37.27 to 50.57; p < 0.00001) and LDL-c (SMD: 33.05 %; 95 % CI 9.08 to 57.01; p = 0.007) levels. There was a significant relative risk reduction in acute pancreatitis in the APOC-III inhibitors group (RR 0.17; 95 % CI 0.05 to 0.53; p = 0.007). Adverse events were similar in both groups.</div></div><div><h3>Conclusion</h3><div>APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156187"},"PeriodicalIF":10.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide with no approved therapy. The development of ALD is strongly associated with hepatic lipid accumulation. Arrestin domain containing 3 (ARRDC3), a member of the α-arrestin family, is involved in obesity, inflammation, and cancer. However, its role in ALD remains largely unexplored.
Methods
Both the NIAAA and traditional Lieber-De Carli mouse models of ALD were employed. ARRDC3 expression was evaluated in liver specimens from ALD patients, mouse hepatic tissues, and hepatocytes. Hepatocyte-targeted Arrdc3 knockdown was achieved through intrahepatic delivery of adeno-associated virus 8 (AAV8) carrying shRNA under a hepatocyte-specific promoter. Mass spectrometry analysis, immunofluorescence, co-immunoprecipitation (co-IP) assays, and molecular docking were used to identify the interaction between ARRDC3 and stearoyl-CoA desaturase 1 (SCD1).
Results
ARRDC3 levels were significantly elevated in the livers of both ALD patients and mouse models. Knockdown of Arrdc3 using AAV8 alleviated alcohol-induced liver steatosis in both the NIAAA and traditional Lieber-De Carli mouse models. We demonstrated that ARRDC3 promoted the progression of ALD by inducing lipid accumulation in hepatocytes. Mechanistically, ARRDC3 directly binds to SCD1 and inhibits its ubiquitin-proteasome degradation. Inhibition of SCD1 blocked ARRDC3-induced lipid deposition in hepatocytes. We also observed a correlation between ARRDC3 and SCD1 in liver samples from ALD patients.
Conclusions
Our findings reveal that ARRDC3 promotes hepatic steatosis in ALD by reducing the ubiquitin-dependent degradation of SCD1. ARRDC3 may serve as a potential therapeutic target for ALD.
{"title":"Arrestin domain containing 3 promotes alcohol-induced liver steatosis by reducing stearoyl-CoA desaturase-1 ubiquitinated degradation","authors":"Ying Tang , Haoxiong Zhou , Xuemei Pan, Zhenwei Zhong, Huiling Liu, Yunwei Guo","doi":"10.1016/j.metabol.2025.156175","DOIUrl":"10.1016/j.metabol.2025.156175","url":null,"abstract":"<div><h3>Background and aims</h3><div>Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide with no approved therapy. The development of ALD is strongly associated with hepatic lipid accumulation. Arrestin domain containing 3 (ARRDC3), a member of the α-arrestin family, is involved in obesity, inflammation, and cancer. However, its role in ALD remains largely unexplored.</div></div><div><h3>Methods</h3><div>Both the NIAAA and traditional Lieber-De Carli mouse models of ALD were employed. ARRDC3 expression was evaluated in liver specimens from ALD patients, mouse hepatic tissues, and hepatocytes. Hepatocyte-targeted <em>Arrdc3</em> knockdown was achieved through intrahepatic delivery of adeno-associated virus 8 (AAV8) carrying shRNA under a hepatocyte-specific promoter. Mass spectrometry analysis, immunofluorescence, co-immunoprecipitation (co-IP) assays, and molecular docking were used to identify the interaction between ARRDC3 and stearoyl-CoA desaturase 1 (SCD1).</div></div><div><h3>Results</h3><div>ARRDC3 levels were significantly elevated in the livers of both ALD patients and mouse models. Knockdown of <em>Arrdc3</em> using AAV8 alleviated alcohol-induced liver steatosis in both the NIAAA and traditional Lieber-De Carli mouse models. We demonstrated that ARRDC3 promoted the progression of ALD by inducing lipid accumulation in hepatocytes. Mechanistically, ARRDC3 directly binds to SCD1 and inhibits its ubiquitin-proteasome degradation. Inhibition of SCD1 blocked ARRDC3-induced lipid deposition in hepatocytes. We also observed a correlation between ARRDC3 and SCD1 in liver samples from ALD patients.</div></div><div><h3>Conclusions</h3><div>Our findings reveal that ARRDC3 promotes hepatic steatosis in ALD by reducing the ubiquitin-dependent degradation of SCD1. ARRDC3 may serve as a potential therapeutic target for ALD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156175"},"PeriodicalIF":10.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-27DOI: 10.1016/j.metabol.2025.156174
Anja Schork , Andreas Fritsche , Erwin D. Schleicher , Andreas Peter , Martin Heni , Norbert Stefan , Reiner Jumpertz von Schwartzenberg , Martina Guthoff , Harald Mischak , Justyna Siwy , Andreas L. Birkenfeld , Robert Wagner
Objective
Individuals at increased risk of type 2 diabetes have recently been classified into six prediabetes clusters, which stratify the risk of progression to diabetes and diabetes complications. Clusters 1, 2 and 4 are low-risk clusters while clusters 3, 5 and 6 are high-risk clusters; individuals in cluster 6 have an elevated risk of nephropathy and all-cause mortality despite delayed onset of diabetes. The urinary peptidome classifiers CKD273 (chronic kidney disease, CKD), HF2 (heart failure, HF) and CAD238 (coronary artery disease, CAD) are based on unique urinary peptide patterns and have shown potential for identifying individuals at risk for CKD and cardiovascular pathologies. This observational study investigates whether peptidome classifiers can differentiate complication risks across the prediabetes clusters and if a novel combination of peptides can distinguish high-risk from low-risk prediabetes clusters.
Methods
Urine peptidome analysis was performed on spot urine samples from individuals across 6 prediabetes clusters (n = 249) and 19 individuals with screen-detected diabetes (study cohorts at University Hospital Tübingen, Germany from 11/2004 to 11/2012). Predefined urinary classifiers were calculated for each participant. Lasso regression analysis was used to identify an optimal combination of peptides distinguishing low- Schlesinger et al. (2022), Wagner et al. (2021) [1,2,4] and high-risk (Rooney et al., 2021; Wagner, 2023; Latosinska et al., 2021 [3,5,6]) clusters.
Results
The predefined urinary peptidome classifiers CKD273, HF2 and CAD238 differed significantly across prediabetes clusters, particularly with elevated values in cluster 6 compared to the healthiest cluster 2. CKD273, HF2 and CAD238 were inversely associated with insulin sensitivity indexes. Machine Learning identified a combination of 112 urinary peptides that differentiated low-risk from high-risk prediabetes clusters (AUC-ROC 0.868 (95 % CI 0.755–0.981)).
Conclusions
Urinary peptidome classifiers support the increased risk of CKD and suggest an elevated risk of heart failure and coronary artery disease in the high-risk prediabetes cluster 6. Urine peptidomics show promising potential as a tool for identifying high-risk prediabetes individuals and guiding early preventive interventions.
{"title":"Differential risk assessment in persons at risk of type 2 diabetes using urinary peptidomics","authors":"Anja Schork , Andreas Fritsche , Erwin D. Schleicher , Andreas Peter , Martin Heni , Norbert Stefan , Reiner Jumpertz von Schwartzenberg , Martina Guthoff , Harald Mischak , Justyna Siwy , Andreas L. Birkenfeld , Robert Wagner","doi":"10.1016/j.metabol.2025.156174","DOIUrl":"10.1016/j.metabol.2025.156174","url":null,"abstract":"<div><h3>Objective</h3><div>Individuals at increased risk of type 2 diabetes have recently been classified into six prediabetes clusters, which stratify the risk of progression to diabetes and diabetes complications. Clusters 1, 2 and 4 are low-risk clusters while clusters 3, 5 and 6 are high-risk clusters; individuals in cluster 6 have an elevated risk of nephropathy and all-cause mortality despite delayed onset of diabetes. The urinary peptidome classifiers CKD273 (chronic kidney disease, CKD), HF2 (heart failure, HF) and CAD238 (coronary artery disease, CAD) are based on unique urinary peptide patterns and have shown potential for identifying individuals at risk for CKD and cardiovascular pathologies. This observational study investigates whether peptidome classifiers can differentiate complication risks across the prediabetes clusters and if a novel combination of peptides can distinguish high-risk from low-risk prediabetes clusters.</div></div><div><h3>Methods</h3><div>Urine peptidome analysis was performed on spot urine samples from individuals across 6 prediabetes clusters (<em>n</em> = 249) and 19 individuals with screen-detected diabetes (study cohorts at University Hospital Tübingen, Germany from 11/2004 to 11/2012). Predefined urinary classifiers were calculated for each participant. Lasso regression analysis was used to identify an optimal combination of peptides distinguishing low- Schlesinger et al. (2022), Wagner et al. (2021) [<span><span>1</span></span>,<span><span>2</span></span>,<span><span>4</span></span>] and high-risk (Rooney et al., 2021; Wagner, 2023; Latosinska et al., 2021 [<span><span>3</span></span>,<span><span>5</span></span>,<span><span>6</span></span>]) clusters.</div></div><div><h3>Results</h3><div>The predefined urinary peptidome classifiers CKD273, HF2 and CAD238 differed significantly across prediabetes clusters, particularly with elevated values in cluster 6 compared to the healthiest cluster 2. CKD273, HF2 and CAD238 were inversely associated with insulin sensitivity indexes. Machine Learning identified a combination of 112 urinary peptides that differentiated low-risk from high-risk prediabetes clusters (AUC-ROC 0.868 (95 % CI 0.755–0.981)).</div></div><div><h3>Conclusions</h3><div>Urinary peptidome classifiers support the increased risk of CKD and suggest an elevated risk of heart failure and coronary artery disease in the high-risk prediabetes cluster 6. Urine peptidomics show promising potential as a tool for identifying high-risk prediabetes individuals and guiding early preventive interventions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156174"},"PeriodicalIF":10.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-22DOI: 10.1016/j.metabol.2025.156173
Dan Zhang , Yang-He Zhang , Bin Liu , Hong-Xia Yang , Guang-Tao Li , Hong-Lan Zhou , Yi-Shu Wang
Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.
{"title":"Role of peroxisomes in the pathogenesis and therapy of renal fibrosis","authors":"Dan Zhang , Yang-He Zhang , Bin Liu , Hong-Xia Yang , Guang-Tao Li , Hong-Lan Zhou , Yi-Shu Wang","doi":"10.1016/j.metabol.2025.156173","DOIUrl":"10.1016/j.metabol.2025.156173","url":null,"abstract":"<div><div>Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156173"},"PeriodicalIF":10.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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