Pub Date : 2024-06-20DOI: 10.1038/s42255-024-01071-2
Subhash C. Pandey, Emir Malovic
In this issue of Nature Metabolism, Fu et al. show that genetic deletion of aldehyde dehydrogenase 2 (ALDH2) simultaneously in the gut and liver synergistically regulates acetaldehyde (AcH) levels and alcohol consumption.
{"title":"Gut–liver highway of ALDH2 in drinking","authors":"Subhash C. Pandey, Emir Malovic","doi":"10.1038/s42255-024-01071-2","DOIUrl":"10.1038/s42255-024-01071-2","url":null,"abstract":"In this issue of Nature Metabolism, Fu et al. show that genetic deletion of aldehyde dehydrogenase 2 (ALDH2) simultaneously in the gut and liver synergistically regulates acetaldehyde (AcH) levels and alcohol consumption.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430513","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 : 2024-06-20DOI: 10.1038/s42255-024-01063-2
Yaojie Fu, Bryan Mackowiak, Yu-Hong Lin, Luca Maccioni, Taylor Lehner, Hongna Pan, Yukun Guan, Grzegorz Godlewski, Hongkun Lu, Cheng Chen, Shoupeng Wei, Dechun Feng, Janos Paloczi, Huiping Zhou, Pal Pacher, Li Zhang, George Kunos, Bin Gao
Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver–gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD. Fu, Mackowiak et al. show that cooperative action of the liver and the gut, rather than the liver alone, drives acetaldehyde clearance after alcohol consumption and modulates drinking behaviour.
酒精使用障碍（AUD）影响着全球数百万人，造成了广泛的发病率和死亡率，但药物治疗效果有限。肝脏被认为是醛脱氢酶 2（ALDH2）对乙醇代谢物乙醛（Acaldehyde，ACH）进行解毒的主要部位，也是治疗酒精中毒性口腔炎（AUD）的靶点，然而，我们最近的数据表明，肝脏在清除全身性乙醛中只发挥了部分作用。在这里，我们发现肝脏-肠道轴（而非仅仅是肝脏）协同推动了全身性乙酰胆碱清除和自愿饮酒。从机理上讲，我们发现摄入乙醇后，肝脏中产生的大部分 AcH 会通过胆汁排泄到胃肠道，在那里 AcH 会被肠道中的 ALDH2 进一步代谢。调节胆汁流量可明显影响血清 AcH 水平和饮酒行为。因此，联合靶向肝脏和肠道 ALDH2 以及调节胆汁流量和分泌是治疗 AUD 的潜在治疗策略。
{"title":"Coordinated action of a gut–liver pathway drives alcohol detoxification and consumption","authors":"Yaojie Fu, Bryan Mackowiak, Yu-Hong Lin, Luca Maccioni, Taylor Lehner, Hongna Pan, Yukun Guan, Grzegorz Godlewski, Hongkun Lu, Cheng Chen, Shoupeng Wei, Dechun Feng, Janos Paloczi, Huiping Zhou, Pal Pacher, Li Zhang, George Kunos, Bin Gao","doi":"10.1038/s42255-024-01063-2","DOIUrl":"10.1038/s42255-024-01063-2","url":null,"abstract":"Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver–gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD. Fu, Mackowiak et al. show that cooperative action of the liver and the gut, rather than the liver alone, drives acetaldehyde clearance after alcohol consumption and modulates drinking behaviour.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430387","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 : 2024-06-19DOI: 10.1038/s42255-024-01065-0
Lucas Massier, Niculina Musat, Michael Stumvoll, Valentina Tremaroli, Rima Chakaroun, Peter Kovacs
Although the impact of the gut microbiome on health and disease is well established, there is controversy regarding the presence of microorganisms such as bacteria and their products in organs and tissues. However, recent contamination-aware findings of tissue-resident microbial signatures provide accumulating evidence in support of bacterial translocation in cardiometabolic disease. The latter provides a distinct paradigm for the link between microbial colonizers of mucosal surfaces and host metabolism. In this Perspective, we re-evaluate the concept of tissue-resident bacteria including their role in metabolic low-grade tissue and systemic inflammation. We examine the limitations and challenges associated with studying low bacterial biomass samples and propose experimental and analytical strategies to overcome these issues. Our Perspective aims to encourage further investigation of the mechanisms linking tissue-resident bacteria to host metabolism and their potentially actionable health implications for prevention and treatment. In this Perspective, the role of tissue-resident bacteria in metabolic diseases is discussed and the experimental challenges that this emerging field is facing are highlighted.
{"title":"Tissue-resident bacteria in metabolic diseases: emerging evidence and challenges","authors":"Lucas Massier, Niculina Musat, Michael Stumvoll, Valentina Tremaroli, Rima Chakaroun, Peter Kovacs","doi":"10.1038/s42255-024-01065-0","DOIUrl":"10.1038/s42255-024-01065-0","url":null,"abstract":"Although the impact of the gut microbiome on health and disease is well established, there is controversy regarding the presence of microorganisms such as bacteria and their products in organs and tissues. However, recent contamination-aware findings of tissue-resident microbial signatures provide accumulating evidence in support of bacterial translocation in cardiometabolic disease. The latter provides a distinct paradigm for the link between microbial colonizers of mucosal surfaces and host metabolism. In this Perspective, we re-evaluate the concept of tissue-resident bacteria including their role in metabolic low-grade tissue and systemic inflammation. We examine the limitations and challenges associated with studying low bacterial biomass samples and propose experimental and analytical strategies to overcome these issues. Our Perspective aims to encourage further investigation of the mechanisms linking tissue-resident bacteria to host metabolism and their potentially actionable health implications for prevention and treatment. In this Perspective, the role of tissue-resident bacteria in metabolic diseases is discussed and the experimental challenges that this emerging field is facing are highlighted.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425269","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 : 2024-06-14DOI: 10.1038/s42255-024-01066-z
Hyun Min Lee, Nefertiti Muhammad, Elizabeth L. Lieu, Feng Cai, Jiawei Mu, Yun-Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S. Ducker, Kellen Olszewski, Ling Cai, Derek B. Allison, Sara E. Bachert, William R. Ewing, Harvey Wong, Hyosun Seo, Isaac Y. Kim, Brandon Faubert, James Kim, Jiyeon Kim
Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies. Lee et al. identify SHMT and one-carbon metabolism as a metabolic vulnerability conferred by LKB1 and KEAP1 loss in KRAS-mutant lung cancer.
{"title":"Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer","authors":"Hyun Min Lee, Nefertiti Muhammad, Elizabeth L. Lieu, Feng Cai, Jiawei Mu, Yun-Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S. Ducker, Kellen Olszewski, Ling Cai, Derek B. Allison, Sara E. Bachert, William R. Ewing, Harvey Wong, Hyosun Seo, Isaac Y. Kim, Brandon Faubert, James Kim, Jiyeon Kim","doi":"10.1038/s42255-024-01066-z","DOIUrl":"10.1038/s42255-024-01066-z","url":null,"abstract":"Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies. Lee et al. identify SHMT and one-carbon metabolism as a metabolic vulnerability conferred by LKB1 and KEAP1 loss in KRAS-mutant lung cancer.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141319849","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 : 2024-06-13DOI: 10.1038/s42255-024-01059-y
Samuel A. Barritt, Sarah E. DuBois-Coyne, Christian C. Dibble
The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K–AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN). This Review summarizes the fundamental aspects related to coenzyme A synthesis and its implications as a central molecule in metabolism.
三羧酸循环、营养物质氧化、组蛋白乙酰化以及脂质、聚糖和血红素的合成都需要辅因子辅酶 A（CoA）。尽管人们对 CoA 所携带的酰基在这些过程中的来源和调控进行了大量研究，但却较少考虑一个关键的基本问题：如何控制 CoA 本身的产生？在这里，我们将讨论 CoA 在细胞中的多种作用，以及在哺乳动物体内从半胱氨酸、ATP 和必需营养素泛酸（维生素 B5）或从残余前体中生物合成 CoA 的调控机制。代谢物反馈和信号机制涉及乙酰-CoA、其他酰基-CoAs、酰基肉碱、MYC、p53、PPARα、PINK1 以及胰岛素和生长因子刺激的 PI3K-AKT 信号，它们调节维生素 B5 转运体 SLC5A6/SMVT 和 CoA 生物合成酶 PANK1、PANK2、PANK3、PANK4 和 COASY。我们还讨论了测量 CoA 相关代谢物的方法、靶向 CoA 生物合成的化合物以及由途径酶突变引起的疾病，包括白内障、心肌病和神经变性（PKAN 和 COPAN）。
{"title":"Coenzyme A biosynthesis: mechanisms of regulation, function and disease","authors":"Samuel A. Barritt, Sarah E. DuBois-Coyne, Christian C. Dibble","doi":"10.1038/s42255-024-01059-y","DOIUrl":"10.1038/s42255-024-01059-y","url":null,"abstract":"The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K–AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN). This Review summarizes the fundamental aspects related to coenzyme A synthesis and its implications as a central molecule in metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315733","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 : 2024-06-13DOI: 10.1038/s42255-024-01061-4
Hüsün S. Kizilkaya, Kimmie V. Sørensen, Jakob S. Madsen, Peter Lindquist, Jonathan D. Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A. Gerlach, Lærke S. Gasbjerg, Jacek Mokrosiński, Stephanie A. Mowery, Patrick J. Knerr, Brian Finan, Jonathan E. Campbell, David A. D’Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J. Holst, Torben Hansen, Shane C. Wright, Volker M. Lauschke, Niels Grarup, Alexander S. Hauser, Mette M. Rosenkilde
Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system. Molecular pharmacological characterization and association testing of human GIPR genetic variants with follow-up analysis in mice shows that β-arrestins regulate GIPR signalling and thereby strongly contribute to metabolic outcomes.
{"title":"Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes","authors":"Hüsün S. Kizilkaya, Kimmie V. Sørensen, Jakob S. Madsen, Peter Lindquist, Jonathan D. Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A. Gerlach, Lærke S. Gasbjerg, Jacek Mokrosiński, Stephanie A. Mowery, Patrick J. Knerr, Brian Finan, Jonathan E. Campbell, David A. D’Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J. Holst, Torben Hansen, Shane C. Wright, Volker M. Lauschke, Niels Grarup, Alexander S. Hauser, Mette M. Rosenkilde","doi":"10.1038/s42255-024-01061-4","DOIUrl":"10.1038/s42255-024-01061-4","url":null,"abstract":"Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system. Molecular pharmacological characterization and association testing of human GIPR genetic variants with follow-up analysis in mice shows that β-arrestins regulate GIPR signalling and thereby strongly contribute to metabolic outcomes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01061-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315587","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 : 2024-06-12DOI: 10.1038/s42255-024-01043-6
Michele Vacca, Ioannis Kamzolas, Lea Mørch Harder, Fiona Oakley, Christian Trautwein, Maximilian Hatting, Trenton Ross, Barbara Bernardo, Anouk Oldenburger, Sara Toftegaard Hjuler, Iwona Ksiazek, Daniel Lindén, Detlef Schuppan, Sergio Rodriguez-Cuenca, Maria Manuela Tonini, Tamara R. Castañeda, Aimo Kannt, Cecília M. P. Rodrigues, Simon Cockell, Olivier Govaere, Ann K. Daly, Michael Allison, Kristian Honnens de Lichtenberg, Yong Ook Kim, Anna Lindblom, Stephanie Oldham, Anne-Christine Andréasson, Franklin Schlerman, Jonathon Marioneaux, Arun Sanyal, Marta B. Afonso, Ramy Younes, Yuichiro Amano, Scott L. Friedman, Shuang Wang, Dipankar Bhattacharya, Eric Simon, Valérie Paradis, Alastair Burt, Ioanna Maria Grypari, Susan Davies, Ann Driessen, Hiroaki Yashiro, Susanne Pors, Maja Worm Andersen, Michael Feigh, Carla Yunis, Pierre Bedossa, Michelle Stewart, Heather L. Cater, Sara Wells, Jörn M. Schattenberg, Quentin M. Anstee, The LITMUS Investigators, Dina Tiniakos, James W. Perfield, Evangelia Petsalaki, Peter Davidsen, Antonio Vidal-Puig
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD ‘human proximity score’ to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research. The LITMUS consortium provides a resource of rodent MASLD models benchmarked against metabolic, histologic and transcriptomic features that are relevant for human MASLD. The work is useful for selecting relevant rodent models for studying this common disease.
{"title":"An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD)","authors":"Michele Vacca, Ioannis Kamzolas, Lea Mørch Harder, Fiona Oakley, Christian Trautwein, Maximilian Hatting, Trenton Ross, Barbara Bernardo, Anouk Oldenburger, Sara Toftegaard Hjuler, Iwona Ksiazek, Daniel Lindén, Detlef Schuppan, Sergio Rodriguez-Cuenca, Maria Manuela Tonini, Tamara R. Castañeda, Aimo Kannt, Cecília M. P. Rodrigues, Simon Cockell, Olivier Govaere, Ann K. Daly, Michael Allison, Kristian Honnens de Lichtenberg, Yong Ook Kim, Anna Lindblom, Stephanie Oldham, Anne-Christine Andréasson, Franklin Schlerman, Jonathon Marioneaux, Arun Sanyal, Marta B. Afonso, Ramy Younes, Yuichiro Amano, Scott L. Friedman, Shuang Wang, Dipankar Bhattacharya, Eric Simon, Valérie Paradis, Alastair Burt, Ioanna Maria Grypari, Susan Davies, Ann Driessen, Hiroaki Yashiro, Susanne Pors, Maja Worm Andersen, Michael Feigh, Carla Yunis, Pierre Bedossa, Michelle Stewart, Heather L. Cater, Sara Wells, Jörn M. Schattenberg, Quentin M. Anstee, The LITMUS Investigators, Dina Tiniakos, James W. Perfield, Evangelia Petsalaki, Peter Davidsen, Antonio Vidal-Puig","doi":"10.1038/s42255-024-01043-6","DOIUrl":"10.1038/s42255-024-01043-6","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD ‘human proximity score’ to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research. The LITMUS consortium provides a resource of rodent MASLD models benchmarked against metabolic, histologic and transcriptomic features that are relevant for human MASLD. The work is useful for selecting relevant rodent models for studying this common disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01043-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309012","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 : 2024-06-12DOI: 10.1038/s42255-024-01052-5
Russell P. Goodman
A centralized metabolic, histologic and transcriptomic evaluation of nearly 40 different murine models of MASH provides a crucial resource for choosing relevant preclinical mouse models for a common liver disease.
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Pub Date : 2024-06-10DOI: 10.1038/s42255-024-01060-5
Lisha Qiu Jin Lim, Lital Adler, Emma Hajaj, Leandro R. Soria, Rotem Ben-Tov Perry, Naama Darzi, Ruchama Brody, Noa Furth, Michal Lichtenstein, Elizabeta Bab-Dinitz, Ziv Porat, Tevie Melman, Alexander Brandis, Sergey Malitsky, Maxim Itkin, Yael Aylon, Shifra Ben-Dor, Irit Orr, Amir Pri-Or, Rony Seger, Yoav Shaul, Eytan Ruppin, Moshe Oren, Minervo Perez, Jordan Meier, Nicola Brunetti-Pierri, Efrat Shema, Igor Ulitsky, Ayelet Erez
Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) in multiple tumors is associated with a poor prognosis partly because of the metabolic diversion of cytosolic aspartate for pyrimidine synthesis, supporting proliferation and mutagenesis owing to nucleotide imbalance. Here, we find that prolonged loss of ASS1 promotes DNA damage in colon cancer cells and fibroblasts from subjects with citrullinemia type I. Following acute induction of DNA damage with doxorubicin, ASS1 expression is elevated in the cytosol and the nucleus with at least a partial dependency on p53; ASS1 metabolically restrains cell cycle progression in the cytosol by restricting nucleotide synthesis. In the nucleus, ASS1 and ASL generate fumarate for the succination of SMARCC1, destabilizing the chromatin-remodeling complex SMARCC1–SNF5 to decrease gene transcription, specifically in a subset of the p53-regulated cell cycle genes. Thus, following DNA damage, ASS1 is part of the p53 network that pauses cell cycle progression, enabling genome maintenance and survival. Loss of ASS1 contributes to DNA damage and promotes cell cycle progression, likely contributing to cancer mutagenesis and, hence, adaptability potential. Lim, Adler et al. show that the urea cycle enzyme ASS1 can function in the nucleus to supply fumarate necessary to drive DNA damage responses.
多种肿瘤中尿素循环酶精氨酸琥珀酸合成酶（ASS1）的下调与不良预后有关，部分原因是细胞质天冬氨酸代谢转用于嘧啶合成，支持核苷酸失衡导致的增殖和突变。在这里，我们发现 ASS1 的长期缺失会促进来自瓜氨酸血症 I 型患者的结肠癌细胞和成纤维细胞中的 DNA 损伤。在使用多柔比星急性诱导 DNA 损伤后，ASS1 在细胞质和细胞核中的表达升高，至少部分依赖于 p53；ASS1 在细胞质中通过限制核苷酸合成来抑制细胞周期的进展。在细胞核中，ASS1 和 ASL 生成富马酸，用于 SMARCC1 的琥珀酸化，从而破坏染色质重塑复合物 SMARCC1-SNF5 的稳定性，减少基因转录，特别是 p53 调控的细胞周期基因子集。因此，DNA损伤后，ASS1是p53网络的一部分，它能暂停细胞周期的进展，使基因组得以维持和存活。ASS1 的缺失会造成 DNA 损伤并促进细胞周期的进展，很可能会导致癌症诱变，进而产生适应潜力。
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