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 de novo 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 Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. 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.
胆汁酸（BA）稳态对各种生理过程至关重要，而胆汁酸紊乱则是胆汁淤积症的根源。法尼类固醇 X 受体（FXR）是通过回肠成纤维细胞生长因子（FGF）15/19 内分泌途径调节胆汁酸平衡的主调节器，对餐后或异常的经肠胆汁酸通量做出反应。然而，在非餐后或肝内胆汁淤积的情况下，肝脏 FXR 的从头旁分泌信号介质控制着肝脏内 BA 的合成程度，但这一介质仍然未知。我们发现肝脏 Fgf4 是 FXR 的直接靶点，它通过旁分泌信号下调 Cyp7a1 和 Cyp8b1。FXR-FGF4的作用是由未知的细胞内FGF受体4（FGFR4）-LRH-1信号节点介导的。这条以肝脏为中心的通路是肝内和跨肝 BA 通路的一线检查点，位于外周 FXR-FGF15/19 通路的上游，共同构成了一个完整的肝肠控制机制，可微调 BA 平衡，抵消胆汁淤积和肝胆损伤。我们的发现为胆汁淤积性疾病的潜在治疗策略提供了启示。
{"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}
G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.
{"title":"Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury","authors":"Hui Lin, Chuanshun Ma, Xiao Zhuang, Shuo Liu, Dong Liu, Mingxiang Zhang, Yan Lu, Guangjian Zhou, Chao Zhang, Tengwei Wang, Zihao Zhang, Lin Lv, Daolai Zhang, Xiong-Zhong Ruan, Yunfei Xu, Renjie Chai, Xiao Yu, Jin-Peng Sun, Bo Chu","doi":"10.1016/j.cmet.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.007","url":null,"abstract":"G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385915","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}
Pub Date : 2024-10-08DOI: 10.1016/j.cmet.2024.09.006
Eishani K. Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel
Endoplasmic reticulum (ER) and inflammatory stress responses contribute to islet dysfunction in type 2 diabetes (T2D). Comprehensive genomic understanding of these human islet stress responses and whether T2D-associated genetic variants modulate them is lacking. Here, comparative transcriptome and epigenome analyses of human islets exposed ex vivo to these stressors revealed 30% of expressed genes and 14% of islet cis-regulatory elements (CREs) as stress responsive, modulated largely in an ER- or cytokine-specific fashion. T2D variants overlapped 86 stress-responsive CREs, including 21 induced by ER stress. We linked the rs6917676-T T2D risk allele to increased islet ER-stress-responsive CRE accessibility and allele-specific β cell nuclear factor binding. MAP3K5, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced β cell apoptosis. Supporting its pro-diabetogenic role, MAP3K5 expression correlated inversely with human islet β cell abundance and was elevated in T2D β cells. This study provides genome-wide insights into human islet stress responses and context-specific T2D variant effects.
{"title":"Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights","authors":"Eishani K. Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel","doi":"10.1016/j.cmet.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.006","url":null,"abstract":"Endoplasmic reticulum (ER) and inflammatory stress responses contribute to islet dysfunction in type 2 diabetes (T2D). Comprehensive genomic understanding of these human islet stress responses and whether T2D-associated genetic variants modulate them is lacking. Here, comparative transcriptome and epigenome analyses of human islets exposed <em>ex vivo</em> to these stressors revealed 30% of expressed genes and 14% of islet <em>cis</em>-regulatory elements (CREs) as stress responsive, modulated largely in an ER- or cytokine-specific fashion. T2D variants overlapped 86 stress-responsive CREs, including 21 induced by ER stress. We linked the rs6917676-T T2D risk allele to increased islet ER-stress-responsive CRE accessibility and allele-specific β cell nuclear factor binding. <em>MAP3K5</em>, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced β cell apoptosis. Supporting its pro-diabetogenic role, <em>MAP3K5</em> expression correlated inversely with human islet β cell abundance and was elevated in T2D β cells. This study provides genome-wide insights into human islet stress responses and context-specific T2D variant effects.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384291","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}
Irritable bowel syndrome with diarrhea (IBS-D) is a common and chronic gastrointestinal disorder that is characterized by abdominal discomfort and occasional diarrhea. The pathogenesis of IBS-D is thought to be related to a combination of factors, including psychological stress, abnormal muscle contractions, and inflammation and disorder of the gut microbiome. However, there is still a lack of comprehensive analysis of the logical regulatory correlation among these factors. In this study, we found that stress induced hyperproduction of xanthine and altered the abundance and metabolic characteristics of Lactobacillus murinus in the gut. Lactobacillus murinus-derived spermidine suppressed the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells by inhibiting the K63-linked polyubiquitination of TRAF3. The reduction in IFN-α unrestricted the contractile function of colonic smooth muscle cells, resulting in an increase in bowel movement. Our findings provided a theoretical basis for the pathological mechanism of, and new drug targets for, stress-exposed IBS-D.
肠易激综合征伴腹泻（IBS-D）是一种常见的慢性胃肠道疾病，以腹部不适和偶尔腹泻为特征。肠易激综合征的发病机制被认为与多种因素有关，包括心理压力、肌肉异常收缩、肠道微生物组的炎症和紊乱。然而，目前仍缺乏对这些因素之间逻辑调控相关性的全面分析。在这项研究中，我们发现压力会诱导黄嘌呤的过度分泌，并改变肠道中鼠乳杆菌的丰度和代谢特征。鼠乳杆菌衍生的亚精胺通过抑制 TRAF3 的 K63 链接多泛素化，抑制了浆细胞树突状细胞中 I 型干扰素（IFN）-α 的基础表达。IFN-α的减少解除了结肠平滑肌细胞的收缩功能，从而增加了肠蠕动。我们的研究结果为压力暴露型 IBS-D 的病理机制和新的药物靶点提供了理论依据。
{"title":"Stress triggers irritable bowel syndrome with diarrhea through a spermidine-mediated decline in type I interferon","authors":"Li Zhang, Hao-li Wang, Ya-fang Zhang, Xin-tao Mao, Ting-ting Wu, Zhi-hui Huang, Wan-jun Jiang, Ke-qi Fan, Dan-dan Liu, Bing Yang, Mei-hui Zhuang, Guang-ming Huang, Yinming Liang, Shu Jeffrey Zhu, Jiang-yan Zhong, Guang-yin Xu, Xiao-ming Li, Qian Cao, Yi-yuan Li, Jin Jin","doi":"10.1016/j.cmet.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.002","url":null,"abstract":"Irritable bowel syndrome with diarrhea (IBS-D) is a common and chronic gastrointestinal disorder that is characterized by abdominal discomfort and occasional diarrhea. The pathogenesis of IBS-D is thought to be related to a combination of factors, including psychological stress, abnormal muscle contractions, and inflammation and disorder of the gut microbiome. However, there is still a lack of comprehensive analysis of the logical regulatory correlation among these factors. In this study, we found that stress induced hyperproduction of xanthine and altered the abundance and metabolic characteristics of <em>Lactobacillus murinus</em> in the gut. <em>Lactobacillus murinus</em>-derived spermidine suppressed the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells by inhibiting the K63-linked polyubiquitination of TRAF3. The reduction in IFN-α unrestricted the contractile function of colonic smooth muscle cells, resulting in an increase in bowel movement. Our findings provided a theoretical basis for the pathological mechanism of, and new drug targets for, stress-exposed IBS-D.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369148","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}
Pub Date : 2024-10-01DOI: 10.1016/j.cmet.2024.09.005
Tuo Shao, Raymond T. Chung
Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with iron metabolism disorders and ferroptosis, but the mechanisms underlying this association remain unclear. Fudi Wang’s group1 used animal models, human cohorts, and multi-omics data to demonstrate the role of iron imbalance in MAFLD and the therapeutic potential of the iron chelator FerroTerminator 1 (FOT1).
{"title":"Ironing out MAFLD: Therapeutic targeting of liver ferroptosis","authors":"Tuo Shao, Raymond T. Chung","doi":"10.1016/j.cmet.2024.09.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.005","url":null,"abstract":"Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with iron metabolism disorders and ferroptosis, but the mechanisms underlying this association remain unclear. Fudi Wang’s group<span><span><sup>1</sup></span></span> used animal models, human cohorts, and multi-omics data to demonstrate the role of iron imbalance in MAFLD and the therapeutic potential of the iron chelator FerroTerminator 1 (FOT1).","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360545","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}
Pub Date : 2024-10-01DOI: 10.1016/j.cmet.2024.09.001
Jessica D. Ewald, Yao Lu, Cara E. Ellis, Jessica Worton, Jelena Kolic, Shugo Sasaki, Dahai Zhang, Theodore dos Santos, Aliya F. Spigelman, Austin Bautista, Xiao-Qing Dai, James G. Lyon, Nancy P. Smith, Jordan M. Wong, Varsha Rajesh, Han Sun, Seth A. Sharp, Jason C. Rogalski, Renata Moravcova, Haoning H. Cen, Patrick E. MacDonald
HumanIslets.com supports diabetes research by offering easy access to islet phenotyping data, analysis tools, and data download. It includes molecular omics, islet and cellular function assays, tissue processing metadata, and phenotypes from 547 donors. As it expands, the resource aims to improve human islet data quality, usability, and accessibility.
{"title":"HumanIslets.com: Improving accessibility, integration, and usability of human research islet data","authors":"Jessica D. Ewald, Yao Lu, Cara E. Ellis, Jessica Worton, Jelena Kolic, Shugo Sasaki, Dahai Zhang, Theodore dos Santos, Aliya F. Spigelman, Austin Bautista, Xiao-Qing Dai, James G. Lyon, Nancy P. Smith, Jordan M. Wong, Varsha Rajesh, Han Sun, Seth A. Sharp, Jason C. Rogalski, Renata Moravcova, Haoning H. Cen, Patrick E. MacDonald","doi":"10.1016/j.cmet.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.001","url":null,"abstract":"HumanIslets.com supports diabetes research by offering easy access to islet phenotyping data, analysis tools, and data download. It includes molecular omics, islet and cellular function assays, tissue processing metadata, and phenotypes from 547 donors. As it expands, the resource aims to improve human islet data quality, usability, and accessibility.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360161","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}
Pub Date : 2024-10-01DOI: 10.1016/j.cmet.2024.09.004
Miguel López
Classically, the central actions of thyroid hormones (THs) on metabolism occur within the hypothalamus. A recent article published in Cell by Sabatini and colleagues demonstrates that TH modulates cerebral cortical circuits of male mice, which might integrate exploratory behavior and whole-body metabolism.
{"title":"Cortical actions of thyroid hormone: An exploration and metabolism crossroad","authors":"Miguel López","doi":"10.1016/j.cmet.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.004","url":null,"abstract":"Classically, the central actions of thyroid hormones (THs) on metabolism occur within the hypothalamus. A recent article published in <em>Cell</em> by Sabatini and colleagues demonstrates that TH modulates cerebral cortical circuits of male mice, which might integrate exploratory behavior and whole-body metabolism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360185","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}
Pub Date : 2024-10-01DOI: 10.1016/j.cmet.2024.09.003
Bandy Chen, Xiaofei Yu, Claudia Horvath-Diano, María José Ortuño, Matthias H. Tschöp, Ania M. Jastreboff, Marc Schneeberger
Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.
{"title":"GLP-1 programs the neurovascular landscape","authors":"Bandy Chen, Xiaofei Yu, Claudia Horvath-Diano, María José Ortuño, Matthias H. Tschöp, Ania M. Jastreboff, Marc Schneeberger","doi":"10.1016/j.cmet.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.09.003","url":null,"abstract":"Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360186","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}
Pub Date : 2024-09-23DOI: 10.1016/j.cmet.2024.08.012
Peng Zhang, Junlai Liu, Allen Lee, Irene Tsaur, Masafumi Ohira, Vivian Duong, Nicholas Vo, Kosuke Watari, Hua Su, Ju Youn Kim, Li Gu, Mandy Zhu, Shabnam Shalapour, Mojgan Hosseini, Gautam Bandyopadhyay, Suling Zeng, Cristina Llorente, Haoqi Nina Zhao, Santosh Lamichhane, Siddharth Mohan, Michael Karin
The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, “gut-liver axis” alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.
{"title":"IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis","authors":"Peng Zhang, Junlai Liu, Allen Lee, Irene Tsaur, Masafumi Ohira, Vivian Duong, Nicholas Vo, Kosuke Watari, Hua Su, Ju Youn Kim, Li Gu, Mandy Zhu, Shabnam Shalapour, Mojgan Hosseini, Gautam Bandyopadhyay, Suling Zeng, Cristina Llorente, Haoqi Nina Zhao, Santosh Lamichhane, Siddharth Mohan, Michael Karin","doi":"10.1016/j.cmet.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.08.012","url":null,"abstract":"The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, “gut-liver axis” alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276831","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}
Pub Date : 2024-09-20DOI: 10.1016/j.cmet.2024.08.010
Xiaoli Wei, Dongqing Wu, Jing Li, Miaomiao Wu, Qianhui Li, Zhaodi Che, Xu Cheng, Qianying Cheng, Fan Yin, Hao Zhang, Xuefu Wang, Shabnam Abtahi, Li Zuo, Lei Hang, Lili Ma, Wei-Ting Kuo, Xiaoying Liu, Jerrold R. Turner, Hua Wang, Jia Xiao, Fei Wang
Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.
{"title":"Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages","authors":"Xiaoli Wei, Dongqing Wu, Jing Li, Miaomiao Wu, Qianhui Li, Zhaodi Che, Xu Cheng, Qianying Cheng, Fan Yin, Hao Zhang, Xuefu Wang, Shabnam Abtahi, Li Zuo, Lei Hang, Lili Ma, Wei-Ting Kuo, Xiaoying Liu, Jerrold R. Turner, Hua Wang, Jia Xiao, Fei Wang","doi":"10.1016/j.cmet.2024.08.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.08.010","url":null,"abstract":"<p>Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid <em>Arrb2</em> deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":29.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273520","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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