Pub Date : 2024-10-14DOI: 10.1038/s42255-024-01151-3
Julio E. Ayala, Owen P. McGuinness, Antentor Hinton Jr
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.
{"title":"David H. Wasserman (1958–2024)","authors":"Julio E. Ayala, Owen P. McGuinness, Antentor Hinton Jr","doi":"10.1038/s42255-024-01151-3","DOIUrl":"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":"6 11","pages":"2025-2026"},"PeriodicalIF":18.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01151-3.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 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
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.
{"title":"Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis","authors":"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","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}
Pub Date : 2024-09-26DOI: 10.1038/s42255-024-01138-0
Paul W. Franks, Daniel E. Coral
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.
{"title":"Causal drivers of human proteome variation in health and disease","authors":"Paul W. Franks, 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}
Pub Date : 2024-09-26DOI: 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
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.
{"title":"Identification and characterization of human GDF15 knockouts","authors":"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","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}
Pub Date : 2024-09-26DOI: 10.1038/s42255-024-01133-5
Julia Carrasco-Zanini, Eleanor Wheeler, Burulça Uluvar, Nicola Kerrison, Mine Koprulu, Nicholas J. Wareham, Maik Pietzner, Claudia Langenberg
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.
{"title":"Mapping biological influences on the human plasma proteome beyond the genome","authors":"Julia Carrasco-Zanini, Eleanor Wheeler, Burulça Uluvar, Nicola Kerrison, Mine Koprulu, Nicholas J. Wareham, Maik Pietzner, 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}
Pub Date : 2024-09-26DOI: 10.1038/s42255-024-01136-2
Samuel N. Breit, Stephen O’Rahilly
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.
{"title":"Humans without GDF15 reassure drug developers","authors":"Samuel N. Breit, 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}
Pub Date : 2024-09-25DOI: 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
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.
肠道微生物群在影响免疫疗法结果方面的关键作用促使人们对潜在的调节剂进行研究。在这里，我们发现口服阿卡波糖能显著提高雌性肿瘤小鼠对抗PD-1疗法的抗肿瘤反应。阿卡波糖能调节肠道微生物群的组成和色氨酸代谢，从而促进趋化因子表达的变化和肿瘤内 T 细胞浸润的增加。我们发现 CD8+ T 细胞是决定联合疗法疗效的关键因素。进一步的实验表明，阿卡波糖可通过 CXCL10-CXCR3 通路促进 CD8+ T 细胞的招募。粪便微生物群移植和肠道微生物群耗竭试验表明，阿卡波糖的作用取决于肠道微生物群。具体来说，阿卡波糖通过色氨酸代谢产物吲哚乙酸盐增强抗PD-1疗法的疗效，吲哚乙酸盐促进CXCL10的表达，从而促进CD8+ T细胞的招募，使肿瘤对抗PD-1疗法敏感。阿卡波糖富集的细菌物种婴儿双歧杆菌也能改善对抗PD-1疗法的反应。总之，我们的研究支持阿卡波糖和抗-PD-1在癌症免疫疗法中的潜在组合。
{"title":"Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota","authors":"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","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}
Pub Date : 2024-09-25DOI: 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
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.
{"title":"Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health","authors":"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","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}
Pub Date : 2024-09-24DOI: 10.1038/s42255-024-01132-6
Gregory D. Cartee
Carapeto et al. provide compelling evidence that exercise can have an inhibitory effect on cellular senescence in the pancreatic islets. Their results clearly demonstrate that serum collected postexercise can induce this effect in islets from either mice or humans.
{"title":"Exercise inhibits cellular senescence in pancreatic islets","authors":"Gregory D. Cartee","doi":"10.1038/s42255-024-01132-6","DOIUrl":"10.1038/s42255-024-01132-6","url":null,"abstract":"Carapeto et al. provide compelling evidence that exercise can have an inhibitory effect on cellular senescence in the pancreatic islets. Their results clearly demonstrate that serum collected postexercise can induce this effect in islets from either mice or humans.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1852-1853"},"PeriodicalIF":18.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313707","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 : 2024-09-24DOI: 10.1038/s42255-024-01130-8
Priscila Carapeto, Kanako Iwasaki, Francesko Hela, Jiho Kahng, Ana B. Alves-Wagner, Roeland J. W. Middelbeek, Michael F. Hirshman, Guy A. Rutter, Laurie J. Goodyear, Cristina Aguayo-Mazzucato
Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on β-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases β-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5′-AMP-activated protein kinase (AMPK) signalling in β-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM. Exercise training decreases pancreatic islet senescence through glucagon and AMPK signalling in mouse and human islets, which could have implications for T2DM therapeutics.
{"title":"Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence","authors":"Priscila Carapeto, Kanako Iwasaki, Francesko Hela, Jiho Kahng, Ana B. Alves-Wagner, Roeland J. W. Middelbeek, Michael F. Hirshman, Guy A. Rutter, Laurie J. Goodyear, Cristina Aguayo-Mazzucato","doi":"10.1038/s42255-024-01130-8","DOIUrl":"10.1038/s42255-024-01130-8","url":null,"abstract":"Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on β-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases β-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5′-AMP-activated protein kinase (AMPK) signalling in β-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM. Exercise training decreases pancreatic islet senescence through glucagon and AMPK signalling in mouse and human islets, which could have implications for T2DM therapeutics.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1976-1990"},"PeriodicalIF":18.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313708","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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