Nature metabolism最新文献

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Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase 伊塔康酸通过抑制琥珀酸脱氢酶驱动 mtRNA 介导的 I 型干扰素产生
IF 20.8 1区 医学
Nature metabolism Pub Date : 2024-10-15 DOI: 10.1038/s42255-024-01145-1
Shane M. O’Carroll, Christian G. Peace, Juliana E. Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J. O’Sullivan, Aline Zoller, Anne F. Mcgettrick, Emily A. Day, Maria Simarro, Neali Armstrong, Justin P. Annes, Luke A. J. O’Neill
{"title":"Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase","authors":"Shane M. O’Carroll, Christian G. Peace, Juliana E. Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J. O’Sullivan, Aline Zoller, Anne F. Mcgettrick, Emily A. Day, Maria Simarro, Neali Armstrong, Justin P. Annes, Luke A. J. O’Neill","doi":"10.1038/s42255-024-01145-1","DOIUrl":"https://doi.org/10.1038/s42255-024-01145-1","url":null,"abstract":"<p>Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"55 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440033","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
Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress 棕色脂肪 ATP-柠檬酸裂解酶将碳水化合物的供应与产热联系起来,并抵御代谢压力
IF 20.8 1区 医学
Nature metabolism Pub Date : 2024-10-14 DOI: 10.1038/s42255-024-01143-3
Ekaterina D. Korobkina, Camila Martinez Calejman, John A. Haley, Miranda E. Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L. Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M. Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R. Green, Paula Vo, Clay F. Semenkovich, Jason R. Pitarresi, Jessica B. Spinelli, Ozkan Aydemir, Christian M. Metallo, Matthew D. Lynes, Cholsoon Jang, Nathaniel W. Snyder, Kathryn E. Wellen, David A. Guertin
{"title":"Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress","authors":"Ekaterina D. Korobkina, Camila Martinez Calejman, John A. Haley, Miranda E. Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L. Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M. Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R. Green, Paula Vo, Clay F. Semenkovich, Jason R. Pitarresi, Jessica B. Spinelli, Ozkan Aydemir, Christian M. Metallo, Matthew D. Lynes, Cholsoon Jang, Nathaniel W. Snyder, Kathryn E. Wellen, David A. Guertin","doi":"10.1038/s42255-024-01143-3","DOIUrl":"https://doi.org/10.1038/s42255-024-01143-3","url":null,"abstract":"<p>Brown adipose tissue (BAT) engages futile fatty acid synthesis–oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY’s role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (<i>Fasn</i>); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting <i>Fasn</i> and <i>Acly</i> unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis–oxidation paradox in BAT.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"13 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431686","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
David H. Wasserman (1958–2024) 戴维-H-瓦瑟曼(1958-2024)
IF 20.8 1区 医学
Nature metabolism Pub Date : 2024-10-14 DOI: 10.1038/s42255-024-01151-3
Julio E. Ayala, Owen P. McGuinness, Antentor Hinton
{"title":"David H. Wasserman (1958–2024)","authors":"Julio E. Ayala, Owen P. McGuinness, Antentor Hinton","doi":"10.1038/s42255-024-01151-3","DOIUrl":"https://doi.org/10.1038/s42255-024-01151-3","url":null,"abstract":"We have lost a distinguished scientist who made indelible contributions to our knowledge of exercise physiology and diabetes and was an advocate for mentoring and transparency in research.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431685","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
Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis 抑制肝脏草酸盐过度生成可改善代谢功能障碍相关性脂肪性肝炎
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-27 DOI: 10.1038/s42255-024-01134-4
Sandeep Das, Alexandra C. Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H. Pearson-Gallion, M. Peyton McKinney, Koral S. E. Richard, Jose A. Gomez-Vidal, Chowdhury S. Abdullah, Elizabeth D. Cockerham, Joseph Eniafe, Andrew D. Yurochko, Tarek Magdy, Christopher B. Pattillo, Christopher G. Kevil, Babak Razani, Md. Shenuarin Bhuiyan, Erin H. Seeley, Gretchen E. Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T. Garcia-Barrio, Philip L. Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A. Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y. Eugene Chen, Nirav Dhanesha, Paul T. Thevenot, Ari J. Cohen, Arif Yurdagul Jr, Oren Rom
{"title":"Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis","authors":"Sandeep Das,&nbsp;Alexandra C. Finney,&nbsp;Sumit Kumar Anand,&nbsp;Sumati Rohilla,&nbsp;Yuhao Liu,&nbsp;Nilesh Pandey,&nbsp;Alia Ghrayeb,&nbsp;Dhananjay Kumar,&nbsp;Kelley Nunez,&nbsp;Zhipeng Liu,&nbsp;Fabio Arias,&nbsp;Ying Zhao,&nbsp;Brenna H. Pearson-Gallion,&nbsp;M. Peyton McKinney,&nbsp;Koral S. E. Richard,&nbsp;Jose A. Gomez-Vidal,&nbsp;Chowdhury S. Abdullah,&nbsp;Elizabeth D. Cockerham,&nbsp;Joseph Eniafe,&nbsp;Andrew D. Yurochko,&nbsp;Tarek Magdy,&nbsp;Christopher B. Pattillo,&nbsp;Christopher G. Kevil,&nbsp;Babak Razani,&nbsp;Md. Shenuarin Bhuiyan,&nbsp;Erin H. Seeley,&nbsp;Gretchen E. Galliano,&nbsp;Bo Wei,&nbsp;Lin Tan,&nbsp;Iqbal Mahmud,&nbsp;Ida Surakka,&nbsp;Minerva T. Garcia-Barrio,&nbsp;Philip L. Lorenzi,&nbsp;Eyal Gottlieb,&nbsp;Eduardo Salido,&nbsp;Jifeng Zhang,&nbsp;A. Wayne Orr,&nbsp;Wanqing Liu,&nbsp;Monica Diaz-Gavilan,&nbsp;Y. Eugene Chen,&nbsp;Nirav Dhanesha,&nbsp;Paul T. Thevenot,&nbsp;Ari J. Cohen,&nbsp;Arif Yurdagul Jr,&nbsp;Oren Rom","doi":"10.1038/s42255-024-01134-4","DOIUrl":"10.1038/s42255-024-01134-4","url":null,"abstract":"The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH. Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1939-1962"},"PeriodicalIF":18.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01134-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325570","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}
引用次数: 0
Causal drivers of human proteome variation in health and disease 健康和疾病中人类蛋白质组变异的因果驱动因素
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-26 DOI: 10.1038/s42255-024-01138-0
Paul W. Franks, Daniel E. Coral
{"title":"Causal drivers of human proteome variation in health and disease","authors":"Paul W. Franks,&nbsp;Daniel E. Coral","doi":"10.1038/s42255-024-01138-0","DOIUrl":"10.1038/s42255-024-01138-0","url":null,"abstract":"In this issue of Nature Metabolism, Carrasco-Zanini et al. describe sets of modifiable and non-modifiable drivers of human plasma proteins. These findings may inform the design of precision prevention programs and highlight novel therapeutic targets.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1854-1855"},"PeriodicalIF":18.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321822","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
Identification and characterization of human GDF15 knockouts 人类 GDF15 基因敲除基因的鉴定和特征描述
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-26 DOI: 10.1038/s42255-024-01135-3
Allan M. Gurtan, Shareef Khalid, Christopher Koch, Maleeha Zaman Khan, Lindsey B. Lamarche, Igor Splawski, Elizabeth Dolan, Ana M. Carrion, Richard Zessis, Matthew E. Clement, Zhiping Chen, Loren D. Lindsley, Yu-Hsin Chiu, Ryan S. Streeper, Daniel P. Denning, Allison B. Goldfine, Brian Doyon, Ali Abbasi, Jennifer L. Harrow, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Alan R. Shuldiner, Juan L. Rodriguez-Flores, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Syed Shahzaib Raza, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, John E. Dominy, Danish Saleheen
{"title":"Identification and characterization of human GDF15 knockouts","authors":"Allan M. Gurtan,&nbsp;Shareef Khalid,&nbsp;Christopher Koch,&nbsp;Maleeha Zaman Khan,&nbsp;Lindsey B. Lamarche,&nbsp;Igor Splawski,&nbsp;Elizabeth Dolan,&nbsp;Ana M. Carrion,&nbsp;Richard Zessis,&nbsp;Matthew E. Clement,&nbsp;Zhiping Chen,&nbsp;Loren D. Lindsley,&nbsp;Yu-Hsin Chiu,&nbsp;Ryan S. Streeper,&nbsp;Daniel P. Denning,&nbsp;Allison B. Goldfine,&nbsp;Brian Doyon,&nbsp;Ali Abbasi,&nbsp;Jennifer L. Harrow,&nbsp;Kazuhisa Tsunoyama,&nbsp;Makoto Asaumi,&nbsp;Ikuyo Kou,&nbsp;Alan R. Shuldiner,&nbsp;Juan L. Rodriguez-Flores,&nbsp;Asif Rasheed,&nbsp;Muhammad Jahanzaib,&nbsp;Muhammad Rehan Mian,&nbsp;Muhammad Bilal Liaqat,&nbsp;Syed Shahzaib Raza,&nbsp;Riffat Sultana,&nbsp;Anjum Jalal,&nbsp;Muhammad Hamid Saeed,&nbsp;Shahid Abbas,&nbsp;Fazal Rehman Memon,&nbsp;Mohammad Ishaq,&nbsp;John E. Dominy,&nbsp;Danish Saleheen","doi":"10.1038/s42255-024-01135-3","DOIUrl":"10.1038/s42255-024-01135-3","url":null,"abstract":"Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3–7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous (‘knockouts’) and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15. This study reports and characterizes the impact of loss-of-function GDF15 variants in human individuals.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1913-1921"},"PeriodicalIF":18.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321824","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
Mapping biological influences on the human plasma proteome beyond the genome 绘制超越基因组的人类血浆蛋白质组生物影响图谱
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-26 DOI: 10.1038/s42255-024-01133-5
Julia Carrasco-Zanini, Eleanor Wheeler, Burulça Uluvar, Nicola Kerrison, Mine Koprulu, Nicholas J. Wareham, Maik Pietzner, Claudia Langenberg
{"title":"Mapping biological influences on the human plasma proteome beyond the genome","authors":"Julia Carrasco-Zanini,&nbsp;Eleanor Wheeler,&nbsp;Burulça Uluvar,&nbsp;Nicola Kerrison,&nbsp;Mine Koprulu,&nbsp;Nicholas J. Wareham,&nbsp;Maik Pietzner,&nbsp;Claudia Langenberg","doi":"10.1038/s42255-024-01133-5","DOIUrl":"10.1038/s42255-024-01133-5","url":null,"abstract":"Broad-capture proteomic platforms now enable simultaneous assessment of thousands of plasma proteins, but most of these are not actively secreted and their origins are largely unknown. Here we integrate genomic with deep phenomic information to identify modifiable and non-modifiable factors associated with 4,775 plasma proteins in ~8,000 mostly healthy individuals. We create a data-driven map of biological influences on the human plasma proteome and demonstrate segregation of proteins into clusters based on major explanatory factors. For over a third (N = 1,575) of protein targets, joint genetic and non-genetic factors explain 10–77% of the variation in plasma (median 19.88%, interquartile range 14.01–31.09%), independent of technical factors (median 2.48%, interquartile range 0.78–6.41%). Together with genetically anchored causal inference methods, our map highlights potential causal associations between modifiable risk factors and plasma proteins for hundreds of protein–disease associations, for example, COL6A3, which possibly mediates the association between reduced kidney function and cardiovascular disease. We provide a map of biological and technical influences on the human plasma proteome to help contextualize findings from proteomic studies. The authors systematically study biological influences on the human plasma proteome in a large cohort, thereby revealing causal associations between plasma proteins and modifiable risk factors for protein–disease associations.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"2010-2023"},"PeriodicalIF":18.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01133-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321826","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}
引用次数: 0
Humans without GDF15 reassure drug developers 不含 GDF15 的人类让药物开发人员放心
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-26 DOI: 10.1038/s42255-024-01136-2
Samuel N. Breit, Stephen O’Rahilly
{"title":"Humans without GDF15 reassure drug developers","authors":"Samuel N. Breit,&nbsp;Stephen O’Rahilly","doi":"10.1038/s42255-024-01136-2","DOIUrl":"10.1038/s42255-024-01136-2","url":null,"abstract":"In this issue of Nature Metabolism, nine people lacking growth differentiation factor 15 (GDF15) from conception are shown to be healthy, with normal development and fertility, providing some reassurance about the safety of blocking GDF15 in conditions like cachexia and pregnancy sickness, where GDF15 contributes to disease pathogenesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1850-1851"},"PeriodicalIF":18.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321825","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
Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota 阿卡波糖通过调节肠道微生物群提高实体瘤免疫疗法的疗效
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-25 DOI: 10.1038/s42255-024-01137-1
Shi-Long Zhang, Xin Wang, Qing-Qing Cai, Chen Chen, Zheng-Yan Zhang, Ya-Yun Xu, Meng-Xuan Yang, Qing-An Jia, Yan Wang, Zhi-Ming Wang
{"title":"Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota","authors":"Shi-Long Zhang,&nbsp;Xin Wang,&nbsp;Qing-Qing Cai,&nbsp;Chen Chen,&nbsp;Zheng-Yan Zhang,&nbsp;Ya-Yun Xu,&nbsp;Meng-Xuan Yang,&nbsp;Qing-An Jia,&nbsp;Yan Wang,&nbsp;Zhi-Ming Wang","doi":"10.1038/s42255-024-01137-1","DOIUrl":"10.1038/s42255-024-01137-1","url":null,"abstract":"The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10–CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy. Oral administration of the anti-diabetic drug acarbose is shown to enhance the efficacy of cancer anti-PD-1 immunotherapy in female mice by modulating the composition and metabolism of the gut microbiota.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1991-2009"},"PeriodicalIF":18.9,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317532","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
Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health 肝脏 X 受体-α的损伤性突变具有肝毒性,并与肝脏健康中的胆固醇感应有关
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-09-25 DOI: 10.1038/s42255-024-01126-4
Sam M. Lockhart, Milan Muso, Ilona Zvetkova, Brian Y. H. Lam, Alessandra Ferrari, Erik Schoenmakers, Katie Duckett, Jack Leslie, Amy Collins, Beatriz Romartínez-Alonso, John A. Tadross, Raina Jia, Eugene J. Gardner, Katherine Kentistou, Yajie Zhao, Felix Day, Alexander Mörseburg, Kara Rainbow, Debra Rimmington, Matteo Mastantuoni, James Harrison, Meritxell Nus, Khalid Guma’a, Sam Sherratt-Mayhew, Xiao Jiang, Katherine R. Smith, Dirk S. Paul, Benjamin Jenkins, Albert Koulman, Maik Pietzner, Claudia Langenberg, Nicholas Wareham, Giles S. Yeo, Krishna Chatterjee, John Schwabe, Fiona Oakley, Derek A. Mann, Peter Tontonoz, Anthony P. Coll, Ken Ong, John R. B. Perry, Stephen O’Rahilly
{"title":"Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health","authors":"Sam M. Lockhart,&nbsp;Milan Muso,&nbsp;Ilona Zvetkova,&nbsp;Brian Y. H. Lam,&nbsp;Alessandra Ferrari,&nbsp;Erik Schoenmakers,&nbsp;Katie Duckett,&nbsp;Jack Leslie,&nbsp;Amy Collins,&nbsp;Beatriz Romartínez-Alonso,&nbsp;John A. Tadross,&nbsp;Raina Jia,&nbsp;Eugene J. Gardner,&nbsp;Katherine Kentistou,&nbsp;Yajie Zhao,&nbsp;Felix Day,&nbsp;Alexander Mörseburg,&nbsp;Kara Rainbow,&nbsp;Debra Rimmington,&nbsp;Matteo Mastantuoni,&nbsp;James Harrison,&nbsp;Meritxell Nus,&nbsp;Khalid Guma’a,&nbsp;Sam Sherratt-Mayhew,&nbsp;Xiao Jiang,&nbsp;Katherine R. Smith,&nbsp;Dirk S. Paul,&nbsp;Benjamin Jenkins,&nbsp;Albert Koulman,&nbsp;Maik Pietzner,&nbsp;Claudia Langenberg,&nbsp;Nicholas Wareham,&nbsp;Giles S. Yeo,&nbsp;Krishna Chatterjee,&nbsp;John Schwabe,&nbsp;Fiona Oakley,&nbsp;Derek A. Mann,&nbsp;Peter Tontonoz,&nbsp;Anthony P. Coll,&nbsp;Ken Ong,&nbsp;John R. B. Perry,&nbsp;Stephen O’Rahilly","doi":"10.1038/s42255-024-01126-4","DOIUrl":"10.1038/s42255-024-01126-4","url":null,"abstract":"Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol. LXRα is highly expressed in hepatocytes, where it regulates cholesterol abundance and stimulates lipogenesis. The authors provide evidence in humans and mice that impaired LXRα signalling is hepatotoxic, despite its potent lipogenic actions.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1922-1938"},"PeriodicalIF":18.9,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01126-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317531","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}
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