Cell metabolismPub Date : 2024-10-28DOI: 10.1016/j.cmet.2024.10.013
Adam J. Rauckhorst, Ryan D. Sheldon, Daniel J. Pape, Adnan Ahmed, Kelly C. Falls-Hubert, Ronald A. Merrill, Reid F. Brown, Kshitij Deshmukh, Thomas A. Vallim, Stanislaw Deja, Shawn C. Burgess, Eric B. Taylor
{"title":"A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones","authors":"Adam J. Rauckhorst, Ryan D. Sheldon, Daniel J. Pape, Adnan Ahmed, Kelly C. Falls-Hubert, Ronald A. Merrill, Reid F. Brown, Kshitij Deshmukh, Thomas A. Vallim, Stanislaw Deja, Shawn C. Burgess, Eric B. Taylor","doi":"10.1016/j.cmet.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.013","url":null,"abstract":"Hepatic <em>de novo</em> lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive <sup>13</sup>C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hexokinase 2 senses fructose in tumor-associated macrophages to promote colorectal cancer growth","authors":"Huiwen Yan, Zhi Wang, Da Teng, Xiaodong Chen, Zijing Zhu, Huan Chen, Wen Wang, Ziyuan Wei, Zhenzhen Wu, Qian Chai, Fei Zhang, Youwang Wang, Kaile Shu, Shaotang Li, Guizhi Shi, Mingzhao Zhu, Hai-long Piao, Xian Shen, Pengcheng Bu","doi":"10.1016/j.cmet.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.002","url":null,"abstract":"Fructose is associated with colorectal cancer tumorigenesis and metastasis through ketohexokinase-mediated metabolism in the colorectal epithelium, yet its role in the tumor immune microenvironment remains largely unknown. Here, we show that a modest amount of fructose, without affecting obesity and associated complications, promotes colorectal cancer tumorigenesis and growth by suppressing the polarization of M1-like macrophages. Fructose inhibits M1-like macrophage polarization independently of fructose-mediated metabolism. Instead, it serves as a signal molecule to promote the interaction between hexokinase 2 and inositol 1,4,5-trisphophate receptor type 3, the predominant Ca<sup>2+</sup> channel on the endoplasmic reticulum. The interaction reduces Ca<sup>2+</sup> levels in cytosol and mitochondria, thereby suppressing the activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1) as well as NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Consequently, this impedes M1-like macrophage polarization. Our study highlights the critical role of fructose as a signaling molecule that impairs the polarization of M1-like macrophages for tumor growth.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Amino acid is a major carbon source for hepatic lipogenesis","authors":"Yilie Liao, Qishan Chen, Lei Liu, Haipeng Huang, Jingyun Sun, Xiaojie Bai, Chenchen Jin, Honghao Li, Fangfang Sun, Xia Xiao, Yahong Zhang, Jia Li, Weiping Han, Suneng Fu","doi":"10.1016/j.cmet.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.001","url":null,"abstract":"Increased <em>de novo</em> lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, <em>ex vivo</em> tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. <em>In vivo</em>, dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-10-24DOI: 10.1016/j.cmet.2024.09.014
Deguan Lv, Deobrat Dixit, Andrea F. Cruz, Leo J.Y. Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C. Gersey, Ryan C. Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L. Kidwell, Xiuxing Wang, Shideng Bao, Housheng H. He, Jeremy N. Rich
{"title":"Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2","authors":"Deguan Lv, Deobrat Dixit, Andrea F. Cruz, Leo J.Y. Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C. Gersey, Ryan C. Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L. Kidwell, Xiuxing Wang, Shideng Bao, Housheng H. He, Jeremy N. Rich","doi":"10.1016/j.cmet.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.014","url":null,"abstract":"Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and <em>in vivo</em> tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-10-22DOI: 10.1016/j.cmet.2024.09.013
Chenxi Zhao, Tingting Zhang, Si-tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li
{"title":"Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex","authors":"Chenxi Zhao, Tingting Zhang, Si-tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li","doi":"10.1016/j.cmet.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.013","url":null,"abstract":"Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-10-21DOI: 10.1016/j.cmet.2024.09.012
Kenichi Sakamoto, Mary A. Butera, Chunxue Zhou, Giulia Maurizi, Bandy Chen, Li Ling, Adham Shawkat, Likhitha Patlolla, Kavira Thakker, Victor Calle, Donald A. Morgan, Kamal Rahmouni, Gary J. Schwartz, Azeddine Tahiri, Christoph Buettner
{"title":"Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity","authors":"Kenichi Sakamoto, Mary A. Butera, Chunxue Zhou, Giulia Maurizi, Bandy Chen, Li Ling, Adham Shawkat, Likhitha Patlolla, Kavira Thakker, Victor Calle, Donald A. Morgan, Kamal Rahmouni, Gary J. Schwartz, Azeddine Tahiri, Christoph Buettner","doi":"10.1016/j.cmet.2024.09.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.012","url":null,"abstract":"The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (<em>th</em>; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-10-15DOI: 10.1016/j.cmet.2024.09.010
Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R. Bornstein, Michael D. Neinast, Caroline R. Bartman, Megan C. Blair, Kristina Li, Chelsea Thorsheim, Joshua D. Rabinowitz, Zoltan Arany
{"title":"Quantification of nutrient fluxes during acute exercise in mice","authors":"Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R. Bornstein, Michael D. Neinast, Caroline R. Bartman, Megan C. Blair, Kristina Li, Chelsea Thorsheim, Joshua D. Rabinowitz, Zoltan Arany","doi":"10.1016/j.cmet.2024.09.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.010","url":null,"abstract":"Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use <em>in vivo</em> steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell metabolismPub Date : 2024-10-15DOI: 10.1016/j.cmet.2024.09.011
Rui Li, Yan Li, Kun Jiang, Lijuan Zhang, Ting Li, Aihua Zhao, Zhuo Zhang, Yale Xia, Kun Ge, Yaqiong Chen, Chengnuo Wang, Weitao Tang, Shuning Liu, Xiaoxi Lin, Yuqin Song, Jie Mei, Chun Xiao, Aoxue Wang, Yejun Zou, Xie Li, Yuzheng Zhao
{"title":"Lighting up arginine metabolism reveals its functional diversity in physiology and pathology","authors":"Rui Li, Yan Li, Kun Jiang, Lijuan Zhang, Ting Li, Aihua Zhao, Zhuo Zhang, Yale Xia, Kun Ge, Yaqiong Chen, Chengnuo Wang, Weitao Tang, Shuning Liu, Xiaoxi Lin, Yuqin Song, Jie Mei, Chun Xiao, Aoxue Wang, Yejun Zou, Xie Li, Yuzheng Zhao","doi":"10.1016/j.cmet.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.011","url":null,"abstract":"Arginine is one of the most metabolically versatile amino acids and plays pivotal roles in diverse biological and pathological processes; however, sensitive tracking of arginine dynamics <em>in situ</em> remains technically challenging. Here, we engineer high-performance fluorescent biosensors, denoted sensitive to arginine (STAR), to illuminate arginine metabolism in cells, mice, and clinical samples. Utilizing STAR, we demonstrate the effects of different amino acids in regulating intra- and extracellular arginine levels. STAR enabled live-cell monitoring of arginine fluctuations during macrophage activation, phagocytosis, efferocytosis, and senescence and revealed cellular senescence depending on arginine availability. Moreover, a simple and fast assay based on STAR revealed that serum arginine levels tended to increase with age, and the elevated serum arginine level is a potential indicator for discriminating the progression and severity of vitiligo. Collectively, our study provides important insights into the metabolic and functional roles of arginine, as well as its potential in diagnostic and therapeutic applications.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress","authors":"Lintao Song, Yushu Hou, Da Xu, Xijia Dai, Jianya Luo, Yi Liu, Zhuobing Huang, Miaomiao Yang, Jie Chen, Yue Hu, Chuchu Chen, Yuli Tang, Zhiheng Rao, Jianjia Ma, Minghua Zheng, Keqing Shi, Chao Cai, Mingqin Lu, Ruqi Tang, Xiong Ma, Zhifeng Huang","doi":"10.1016/j.cmet.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.008","url":null,"abstract":"Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the <em>de novo</em> paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic <em>Fgf4</em> as a direct FXR target that paracrinally signals to downregulate <em>Cyp7a1</em> and <em>Cyp8b1</em>. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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