Nature metabolism最新文献_第2页

Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells 多重基因组编辑在不影响哺乳动物细胞生长速率的情况下消除了乳酸的产生

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-14 DOI: 10.1038/s42255-024-01193-7

Hooman Hefzi, Iván Martínez-Monge, Igor Marin de Mas, Nicholas Luke Cowie, Alejandro Gomez Toledo, Soo Min Noh, Karen Julie la Cour Karottki, Marianne Decker, Johnny Arnsdorf, Jose Manuel Camacho-Zaragoza, Stefan Kol, Sanne Schoffelen, Nuša Pristovšek, Anders Holmgaard Hansen, Antonio A. Miguez, Sara Petersen Bjørn, Karen Kathrine Brøndum, Elham Maria Javidi, Kristian Lund Jensen, Laura Stangl, Emanuel Kreidl, Thomas Beuchert Kallehauge, Daniel Ley, Patrice Ménard, Helle Munck Petersen, Zulfiya Sukhova, Anton Bauer, Emilio Casanova, Niall Barron, Johan Malmström, Lars K. Nielsen, Gyun Min Lee, Helene Faustrup Kildegaard, Bjørn G. Voldborg, Nathan E. Lewis

{"title":"Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells","authors":"Hooman Hefzi, Iván Martínez-Monge, Igor Marin de Mas, Nicholas Luke Cowie, Alejandro Gomez Toledo, Soo Min Noh, Karen Julie la Cour Karottki, Marianne Decker, Johnny Arnsdorf, Jose Manuel Camacho-Zaragoza, Stefan Kol, Sanne Schoffelen, Nuša Pristovšek, Anders Holmgaard Hansen, Antonio A. Miguez, Sara Petersen Bjørn, Karen Kathrine Brøndum, Elham Maria Javidi, Kristian Lund Jensen, Laura Stangl, Emanuel Kreidl, Thomas Beuchert Kallehauge, Daniel Ley, Patrice Ménard, Helle Munck Petersen, Zulfiya Sukhova, Anton Bauer, Emilio Casanova, Niall Barron, Johan Malmström, Lars K. Nielsen, Gyun Min Lee, Helene Faustrup Kildegaard, Bjørn G. Voldborg, Nathan E. Lewis","doi":"10.1038/s42255-024-01193-7","DOIUrl":"https://doi.org/10.1038/s42255-024-01193-7","url":null,"abstract":"The Warburg effect, which describes the fermentation of glucose to lactate even in the presence of oxygen, is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production in cells for bioprocessing have failed as lactate dehydrogenase is essential for cell growth. Here, we effectively eliminate lactate production in Chinese hamster ovary and in the human embryonic kidney cell line HEK293 by simultaneous knockout of lactate dehydrogenases and pyruvate dehydrogenase kinases, thereby removing a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. These cells, which we refer to as Warburg-null cells, maintain wild-type growth rates while producing negligible lactate, show a compensatory increase in oxygen consumption, near total reliance on oxidative metabolism, and higher cell densities in fed-batch cell culture. Warburg-null cells remain amenable for production of diverse biotherapeutic proteins, reaching industrially relevant titres and maintaining product glycosylation. The ability to eliminate lactate production may be useful for biotherapeutic production and provides a tool for investigating a common metabolic phenomenon.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"76 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975087","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}

引用次数: 0

Diabetes in China: epidemiology, pathophysiology and multi-omics 中国的糖尿病：流行病学、病理生理学和多组学

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-14 DOI: 10.1038/s42255-024-01190-w

Weiping Jia, Juliana CN Chan, Tien Y. Wong, Edwin B. Fisher

引用次数: 0

Early prediction of healthy ageing and age-related diseases using blood protein biomarkers 利用血液蛋白生物标志物对健康老龄化和年龄相关疾病进行早期预测

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-13 DOI: 10.1038/s42255-024-01199-1

引用次数: 0

Longitudinal serum proteome mapping reveals biomarkers for healthy ageing and related cardiometabolic diseases 纵向血清蛋白质组图谱揭示了健康衰老和相关心脏代谢疾病的生物标志物

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-13 DOI: 10.1038/s42255-024-01185-7

Jun Tang, Liang Yue, Ying Xu, Fengzhe Xu, Xue Cai, Yuanqing Fu, Zelei Miao, Wanglong Gou, Wei Hu, Zhangzhi Xue, Kui Deng, Luqi Shen, Zengliang Jiang, Menglei Shuai, Xinxiu Liang, Congmei Xiao, Yuting Xie, Tiannan Guo, Yu-ming Chen, Ju-Sheng Zheng

{"title":"Longitudinal serum proteome mapping reveals biomarkers for healthy ageing and related cardiometabolic diseases","authors":"Jun Tang, Liang Yue, Ying Xu, Fengzhe Xu, Xue Cai, Yuanqing Fu, Zelei Miao, Wanglong Gou, Wei Hu, Zhangzhi Xue, Kui Deng, Luqi Shen, Zengliang Jiang, Menglei Shuai, Xinxiu Liang, Congmei Xiao, Yuting Xie, Tiannan Guo, Yu-ming Chen, Ju-Sheng Zheng","doi":"10.1038/s42255-024-01185-7","DOIUrl":"https://doi.org/10.1038/s42255-024-01185-7","url":null,"abstract":"The blood proteome contains biomarkers of ageing and age-associated diseases, but such markers are rarely validated longitudinally. Here we map the longitudinal proteome in 7,565 serum samples from a cohort of 3,796 middle-aged and elderly adults across three time points over a 9-year follow-up period. We pinpoint 86 ageing-related proteins that exhibit signatures associated with 32 clinical traits and the incidence of 14 major ageing-related chronic diseases. Leveraging a machine-learning model, we pick 22 of these proteins to generate a proteomic healthy ageing score (PHAS), capable of predicting the incidence of cardiometabolic diseases. We further identify the gut microbiota as a modifiable factor influencing the PHAS. Our data constitute a valuable resource and offer useful insights into the roles of serum proteins in ageing and age-associated cardiometabolic diseases, providing potential targets for intervention with therapeutics to promote healthy ageing.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"29 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968263","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}

引用次数: 0

The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes 戊糖磷酸途径控制氧化蛋白折叠并防止软骨细胞中的铁下垂

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-10 DOI: 10.1038/s42255-024-01187-5

Shauni Loopmans, Katerina Rohlenova, Thomas van Brussel, Ingrid Stockmans, Karen Moermans, Nicolas Peredo, Peter Carmeliet, Diether Lambrechts, Steve Stegen, Geert Carmeliet

{"title":"The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes","authors":"Shauni Loopmans, Katerina Rohlenova, Thomas van Brussel, Ingrid Stockmans, Karen Moermans, Nicolas Peredo, Peter Carmeliet, Diether Lambrechts, Steve Stegen, Geert Carmeliet","doi":"10.1038/s42255-024-01187-5","DOIUrl":"https://doi.org/10.1038/s42255-024-01187-5","url":null,"abstract":"Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"67 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961485","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}

引用次数: 0

TM6SF2 as new intestinal lipid player TM6SF2作为新型肠道脂质抑制剂

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-10 DOI: 10.1038/s42255-024-01156-y

Herbert Tilg, Christoph Grander

引用次数: 0

Divergent roles for propionate and butyrate in colorectal cancer epigenetics 丙酸盐和丁酸盐在结直肠癌表观遗传学中的不同作用

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-09 DOI: 10.1038/s42255-024-01186-6

Yuen Jian Cheong, Sophie Trefely

引用次数: 0

Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression 短链脂肪酸代谢物丙酸酯和丁酸酯是连接饮食、代谢和基因表达的独特表观遗传调控元件

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-09 DOI: 10.1038/s42255-024-01191-9

Michael Nshanian, Joshua J. Gruber, Benjamin S. Geller, Faye Chleilat, Samuel M. Lancaster, Shannon M. White, Ludmila Alexandrova, Jeannie M. Camarillo, Neil L. Kelleher, Yingming Zhao, Michael P. Snyder

{"title":"Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression","authors":"Michael Nshanian, Joshua J. Gruber, Benjamin S. Geller, Faye Chleilat, Samuel M. Lancaster, Shannon M. White, Ludmila Alexandrova, Jeannie M. Camarillo, Neil L. Kelleher, Yingming Zhao, Michael P. Snyder","doi":"10.1038/s42255-024-01191-9","DOIUrl":"https://doi.org/10.1038/s42255-024-01191-9","url":null,"abstract":"The short-chain fatty acids (SCFAs) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. To better understand the function of these modifications, we used chromatin immunoprecipitation followed by sequencing to map the genome-wide location of four short-chain acyl histone marks, H3K18pr, H3K18bu, H4K12pr and H4K12bu, in treated and untreated colorectal cancer (CRC) and normal cells as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions and gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation and ion transport. We propose a mechanism involving direct modification of specific genomic regions by SCFAs resulting in increased chromatin accessibility and, in the case of butyrate, opposing effects on the proliferation of normal versus CRC cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"37 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936910","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}

引用次数: 0

Cellular and organismal function of choline metabolism 胆碱代谢的细胞和机体功能

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-08 DOI: 10.1038/s42255-024-01203-8

Timothy C. Kenny, Samantha Scharenberg, Monther Abu-Remaileh, Kıvanç Birsoy

{"title":"Cellular and organismal function of choline metabolism","authors":"Timothy C. Kenny, Samantha Scharenberg, Monther Abu-Remaileh, Kıvanç Birsoy","doi":"10.1038/s42255-024-01203-8","DOIUrl":"https://doi.org/10.1038/s42255-024-01203-8","url":null,"abstract":"Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"20 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935724","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}

引用次数: 0

Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut–liver axis 肠道TM6SF2通过肠-肝轴保护代谢功能障碍相关的脂肪性肝炎

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-01-08 DOI: 10.1038/s42255-024-01177-7

Xiang Zhang, Harry Cheuk-Hay Lau, Suki Ha, Chuanfa Liu, Cong Liang, Hye Won Lee, Queena Wing-Yin Ng, Yi Zhao, Fenfen Ji, Yunfei Zhou, Yasi Pan, Yang Song, Yating Zhang, Jennie Ching Yin Lo, Alvin Ho Kwan Cheung, Jianfeng Wu, Xiaoxing Li, Hongzhi Xu, Chi Chun Wong, Vincent Wai-Sun Wong, Jun Yu

{"title":"Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut–liver axis","authors":"Xiang Zhang, Harry Cheuk-Hay Lau, Suki Ha, Chuanfa Liu, Cong Liang, Hye Won Lee, Queena Wing-Yin Ng, Yi Zhao, Fenfen Ji, Yunfei Zhou, Yasi Pan, Yang Song, Yating Zhang, Jennie Ching Yin Lo, Alvin Ho Kwan Cheung, Jianfeng Wu, Xiaoxing Li, Hongzhi Xu, Chi Chun Wong, Vincent Wai-Sun Wong, Jun Yu","doi":"10.1038/s42255-024-01177-7","DOIUrl":"https://doi.org/10.1038/s42255-024-01177-7","url":null,"abstract":"Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is associated with metabolic dysfunction-associated steatohepatitis (MASH). TM6SF2 genetic variants are associated with steatotic liver disease. The pathogenesis of MASH involves genetic factors and gut microbiota alteration, yet the role of host–microbe interactions in MASH development remains unclear. Here, we discover that mice with intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2ΔIEC) develop MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2ΔIEC mice induces steatohepatitis in germ-free recipient mice, whereas MASH is alleviated in Tm6sf2ΔIEC mice co-housed with wild-type mice. Mechanistically, Tm6sf2-deficient intestinal cells secrete more free fatty acids by interacting with fatty acid-binding protein 5 to induce intestinal barrier dysfunction, enrichment of pathobionts, and elevation of lysophosphatidic acid (LPA) levels. LPA is translocated from the gut to the liver, contributing to lipid accumulation and inflammation. Pharmacological inhibition of the LPA receptor suppresses MASH in both Tm6sf2ΔIEC and wild-type mice. Hence, modulating microbiota or blocking the LPA receptor is a potential therapeutic strategy in TM6SF2 deficiency-induced MASH.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"35 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935723","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}

引用次数: 0