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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 18.9 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":"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. Intestinal TM6SF2 is found to interact with fatty acid-binding protein 5 to modulate the secretion of fatty acids and the composition of the gut microbiota, thereby protecting against metabolic dysfunction-associated steatohepatitis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"102-119"},"PeriodicalIF":18.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01177-7.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Career pathways, part 16 职业道路,第16部分
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-07 DOI: 10.1038/s42255-024-01192-8
Cholsoon Jang, Min-Dian Li
{"title":"Career pathways, part 16","authors":"Cholsoon Jang, Min-Dian Li","doi":"10.1038/s42255-024-01192-8","DOIUrl":"10.1038/s42255-024-01192-8","url":null,"abstract":"In this instalment of our Career Pathways series, Cholsoon Jang and Min-Dian Li share how curiosity from a very early age has driven their scientific journeys.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 2","pages":"231-233"},"PeriodicalIF":18.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934887","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 hepatic clock synergizes with HIF-1α to regulate nucleotide availability during liver damage repair 肝时钟与HIF-1α协同调节肝损伤修复过程中的核苷酸可用性
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-07 DOI: 10.1038/s42255-024-01184-8
Linyuan Peng, Siliang Xiang, Tianzhi Wang, Mei Yang, Yajun Duan, Xiaoyu Ma, Su Li, Cong Yu, Xin Zhang, Haiyang Hu, Zuojun Liu, Jie Sun, Chunmeng Sun, Chen Wang, Baohua Liu, Zhongyuan Wang, Minxian Qian
{"title":"The hepatic clock synergizes with HIF-1α to regulate nucleotide availability during liver damage repair","authors":"Linyuan Peng, Siliang Xiang, Tianzhi Wang, Mei Yang, Yajun Duan, Xiaoyu Ma, Su Li, Cong Yu, Xin Zhang, Haiyang Hu, Zuojun Liu, Jie Sun, Chunmeng Sun, Chen Wang, Baohua Liu, Zhongyuan Wang, Minxian Qian","doi":"10.1038/s42255-024-01184-8","DOIUrl":"10.1038/s42255-024-01184-8","url":null,"abstract":"Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit DNA replication stress to limit liver regeneration after resection but also allow genotoxin-induced hepatocyte senescence and STING signalling-dependent inflammation. Mechanistically, the molecular clock activator BMAL1 synergizes with hypoxia-inducible factor-1α (HIF-1α) to regulate the transcription of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), which is enhanced during liver regeneration. Overexpressing G6PD restores the compromised regenerative capacity of the BMAL1- or HIF-1α-deficient liver. Moreover, boosting G6PD expression genetically or through preoperative intermittent fasting potently facilitates liver repair in normal mice. Hence, our findings highlight the physiological importance of the hepatic clock and suggest a promising pro-regenerative strategy. During liver damage repair, the circadian clock in the liver is shown to act together with HIF-1α signalling to regulate pentose phosphate pathway activity and nucleotide availability.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"148-165"},"PeriodicalIF":18.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934990","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
Making sense of gene expression control by flux sensing 通量传感基因表达控制的意义
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-06 DOI: 10.1038/s42255-024-01182-w
Bas Teusink, Robert Planqué, Frank J. Bruggeman
{"title":"Making sense of gene expression control by flux sensing","authors":"Bas Teusink, Robert Planqué, Frank J. Bruggeman","doi":"10.1038/s42255-024-01182-w","DOIUrl":"10.1038/s42255-024-01182-w","url":null,"abstract":"Cells regulate metabolic fluxes by changing enzyme levels according to their needs, but how do they regulate something that cannot be measured directly? In this issue of Nature Metabolism, Palme et al. address the fundamental question of how metabolic flux sensing is coupled to gene expression.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"8-10"},"PeriodicalIF":18.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929419","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 galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation 酵母的半乳糖激酶通过感知代谢通量来稳定半乳糖通路的调控
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-06 DOI: 10.1038/s42255-024-01181-x
Julius Palme, Ang Li, Michael Springer
{"title":"The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation","authors":"Julius Palme, Ang Li, Michael Springer","doi":"10.1038/s42255-024-01181-x","DOIUrl":"10.1038/s42255-024-01181-x","url":null,"abstract":"Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction. However, in the galactose-responsive (GAL) pathway of Saccharomyces cerevisiae, we find that induction is stabilized by flux sensing. Previously proposed mechanisms for flux sensing postulate the existence of metabolites whose concentrations correlate with flux. The GAL pathway flux sensor uses a different principle: the galactokinase Gal1p both performs the first step in GAL metabolism and reports on flux by signalling to the GAL repressor, Gal80p. Both Gal1p catalysis and Gal1p signalling depend on the concentration of the Gal1p–GAL complex and are therefore directly correlated. Given the simplicity of this mechanism, flux sensing is probably a general feature throughout metabolic regulation. Palme et al. investigate the fundamental principles that enable metabolic flux sensing in yeast.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"137-147"},"PeriodicalIF":18.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01181-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929422","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
Holistic approaches to explain and combat obesity 解释和对抗肥胖的整体方法
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-03 DOI: 10.1038/s42255-024-01197-3
Tobias Anker Stripp, Per Torp Sangild
{"title":"Holistic approaches to explain and combat obesity","authors":"Tobias Anker Stripp, Per Torp Sangild","doi":"10.1038/s42255-024-01197-3","DOIUrl":"10.1038/s42255-024-01197-3","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"1-2"},"PeriodicalIF":18.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916899","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
Pivotal role of exogenous pyruvate in human natural killer cell metabolism 外源性丙酮酸在人体自然杀伤细胞代谢中的关键作用
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-03 DOI: 10.1038/s42255-024-01188-4
Nicolas Kern Coquillat, Louis Picq, Ameline Hamond, Pierre Megy, Sarah Benezech, Annabelle Drouillard, Nina Lager-Lachaud, Edern Cahoreau, Marielle Moreau, Lucie Fallone, Anne-Laure Mathieu, Floriant Bellvert, Carine Nizard, Anne-Laure Bulteau, Thierry Walzer, Antoine Marçais
{"title":"Pivotal role of exogenous pyruvate in human natural killer cell metabolism","authors":"Nicolas Kern Coquillat, Louis Picq, Ameline Hamond, Pierre Megy, Sarah Benezech, Annabelle Drouillard, Nina Lager-Lachaud, Edern Cahoreau, Marielle Moreau, Lucie Fallone, Anne-Laure Mathieu, Floriant Bellvert, Carine Nizard, Anne-Laure Bulteau, Thierry Walzer, Antoine Marçais","doi":"10.1038/s42255-024-01188-4","DOIUrl":"10.1038/s42255-024-01188-4","url":null,"abstract":"Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability. Glucose-derived carbons do not generate endogenous pyruvate. Consequently, NK cells import extracellular pyruvate that is reduced to lactate to regenerate glycolytic NAD+ and is oxidized in the tricarboxylic acid (TCA) cycle to produce ATP. This supports serine production through phosphoglycerate dehydrogenase, a pathway required for optimal proliferation following cytokine stimulation but dispensable for effector functions. In addition, like mouse NK cells, human NK cells rely on a citrate–malate configuration of the TCA cycle that is not fed by glutamine. Moreover, supraphysiologic pyruvate concentrations dose-dependently increase the effector functions of NK cells. Overall, this study highlights the role of exogenous pyruvate in NK cell biology, providing knowledge that could be exploited to boost NK cell potential in therapeutic settings. Kern Coquillat et al. show that NK cells rely on exogenous pyruvate import to support effector functions.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 2","pages":"336-347"},"PeriodicalIF":18.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917290","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
NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis NUFIP1整合了氨基酸感知和DNA损伤反应来维持肠道内稳态
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-03 DOI: 10.1038/s42255-024-01179-5
Hui Ming, Jing Tan, Si-Yi Cao, Cheng-Ping Yu, Yu-Ting Qi, Chao Wang, Lei Zhang, Ying Liu, Jian Yuan, Miao Yin, Qun-Ying Lei
{"title":"NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis","authors":"Hui Ming, Jing Tan, Si-Yi Cao, Cheng-Ping Yu, Yu-Ting Qi, Chao Wang, Lei Zhang, Ying Liu, Jian Yuan, Miao Yin, Qun-Ying Lei","doi":"10.1038/s42255-024-01179-5","DOIUrl":"10.1038/s42255-024-01179-5","url":null,"abstract":"Nutrient availability strongly affects intestinal homeostasis. Here, we report that low-protein (LP) diets decrease amino acids levels, impair the DNA damage response (DDR), cause DNA damage and exacerbate inflammation in intestinal tissues of male mice with inflammatory bowel disease (IBD). Intriguingly, loss of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1) contributes to the amino acid deficiency-induced impairment of the DDR in vivo and in vitro and induces necroptosis-related spontaneous enteritis. Mechanistically, phosphorylated NUFIP1 binds to replication protein A2 (RPA32) to recruit the ataxia telangiectasia and Rad3-related (ATR)–ATR-interacting protein (ATRIP) complex, triggering the DDR. Consistently, both reintroducing NUFIP1 but not its non-phospho-mutant and inhibition of necroptosis prevent bowel inflammation in male Nufip1 conditional knockout mice. Intestinal inflammation and DNA damage in male mice with IBD can be mitigated by NUFIP1 overexpression. Moreover, NUFIP1 protein levels in the intestine of patients with IBD were found to be significantly decreased. Conclusively, our study uncovers that LP diets contribute to intestinal inflammation by hijacking NUFIP1–DDR signalling and thereby activating necroptosis. Under low-protein conditions, decrease of protein NUFIP1 is found to impair DNA damage response and induce necroptosis in the intestine, thereby contributing to intestinal inflammation in male mice with inflammatory bowel disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"120-136"},"PeriodicalIF":18.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916900","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
Natural killer loops: pyruvate in, lactate out 自然杀手循环:丙酮酸进,乳酸酸出
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-03 DOI: 10.1038/s42255-024-01195-5
Cathal Keane, David K. Finlay
{"title":"Natural killer loops: pyruvate in, lactate out","authors":"Cathal Keane, David K. Finlay","doi":"10.1038/s42255-024-01195-5","DOIUrl":"10.1038/s42255-024-01195-5","url":null,"abstract":"Resting human CD56Dim natural killer cells utilize exogenous pyruvate to support energy metabolism. A new study shows that these cells take up exogenous pyruvate, which regenerates cytosolic NAD+ via metabolism to lactate to support glycolysis and fuels oxidative phosphorylation via the mitochondrial citrate–malate shuttle.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 2","pages":"239-241"},"PeriodicalIF":18.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917259","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
Do not overlook the role of fructose in obesity 不要忽视果糖在肥胖中的作用
IF 18.9 1区 医学
Nature metabolism Pub Date : 2025-01-03 DOI: 10.1038/s42255-024-01198-2
Takahiko Nakagawa, Richard J. Johnson
{"title":"Do not overlook the role of fructose in obesity","authors":"Takahiko Nakagawa, Richard J. Johnson","doi":"10.1038/s42255-024-01198-2","DOIUrl":"10.1038/s42255-024-01198-2","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":"3-3"},"PeriodicalIF":18.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916898","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
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