IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26638-5.html
   My bibliography  Save this article

The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis

Author

Listed:
  • Motohiro Sekiya

    (University of Tsukuba)

  • Kenta Kainoh

    (University of Tsukuba)

  • Takehito Sugasawa

    (University of Tsukuba)

  • Ryunosuke Yoshino

    (University of Tsukuba)

  • Takatsugu Hirokawa

    (University of Tsukuba)

  • Hiroaki Tokiwa

    (Rikkyo University, Nishi-Ikebukuro)

  • Shogo Nakano

    (University of Shizuoka)

  • Satoru Nagatoishi

    (The University of Tokyo)

  • Kouhei Tsumoto

    (The University of Tokyo
    The University of Tokyo)

  • Yoshinori Takeuchi

    (University of Tsukuba)

  • Takafumi Miyamoto

    (University of Tsukuba)

  • Takashi Matsuzaka

    (University of Tsukuba
    University of Tsukuba)

  • Hitoshi Shimano

    (University of Tsukuba)

Abstract

Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.

Suggested Citation

  • Motohiro Sekiya & Kenta Kainoh & Takehito Sugasawa & Ryunosuke Yoshino & Takatsugu Hirokawa & Hiroaki Tokiwa & Shogo Nakano & Satoru Nagatoishi & Kouhei Tsumoto & Yoshinori Takeuchi & Takafumi Miyamot, 2021. "The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26638-5
    DOI: 10.1038/s41467-021-26638-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26638-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26638-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Johayra Simithy & Simone Sidoli & Zuo-Fei Yuan & Mariel Coradin & Natarajan V. Bhanu & Dylan M. Marchione & Brianna J. Klein & Gleb A. Bazilevsky & Cheryl E. McCullough & Robert S. Magin & Tatiana G. , 2017. "Characterization of histone acylations links chromatin modifications with metabolism," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    2. Rachel J. Perry & Dongyan Zhang & Mateus T. Guerra & Allison L. Brill & Leigh Goedeke & Ali R. Nasiri & Aviva Rabin-Court & Yongliang Wang & Liang Peng & Sylvie Dufour & Ye Zhang & Xian-Man Zhang & Gi, 2020. "Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis," Nature, Nature, vol. 579(7798), pages 279-283, March.
    3. Christoph J. Wienken & Philipp Baaske & Ulrich Rothbauer & Dieter Braun & Stefan Duhr, 2010. "Protein-binding assays in biological liquids using microscale thermophoresis," Nature Communications, Nature, vol. 1(1), pages 1-7, December.
    4. Evan D. Rosen & Bruce M. Spiegelman, 2006. "Adipocytes as regulators of energy balance and glucose homeostasis," Nature, Nature, vol. 444(7121), pages 847-853, December.
    5. Tilman Oltersdorf & Steven W. Elmore & Alexander R. Shoemaker & Robert C. Armstrong & David J. Augeri & Barbara A. Belli & Milan Bruncko & Thomas L. Deckwerth & Jurgen Dinges & Philip J. Hajduk & Mary, 2005. "An inhibitor of Bcl-2 family proteins induces regression of solid tumours," Nature, Nature, vol. 435(7042), pages 677-681, June.
    6. Anila K. Madiraju & Derek M. Erion & Yasmeen Rahimi & Xian-Man Zhang & Demetrios T. Braddock & Ronald A. Albright & Brett J. Prigaro & John L. Wood & Sanjay Bhanot & Michael J. MacDonald & Michael J. , 2014. "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase," Nature, Nature, vol. 510(7506), pages 542-546, June.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Nishit Goradia & Stefan Werner & Edukondalu Mullapudi & Sarah Greimeier & Lina Bergmann & Andras Lang & Haydyn Mertens & Aleksandra Węglarz & Simon Sander & Grzegorz Chojnowski & Harriet Wikman & Oliv, 2024. "Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Joyce S. Ramos & Lance C. Dalleck & Caitlin E. Keith & Mackenzie Fennell & Zoe Lee & Claire Drummond & Shelley E. Keating & Robert G. Fassett & Jeff S. Coombes, 2020. "Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial," IJERPH, MDPI, vol. 17(10), pages 1-14, May.
    2. Georg Krainer & Kadi L. Saar & William E. Arter & Timothy J. Welsh & Magdalena A. Czekalska & Raphaël P. B. Jacquat & Quentin Peter & Walther C. Traberg & Arvind Pujari & Akhila K. Jayaram & Pavankuma, 2023. "Direct digital sensing of protein biomarkers in solution," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Melkaye G Melka & Michal Abrahamowicz & Gabriel T Leonard & Michel Perron & Louis Richer & Suzanne Veillette & Daniel Gaudet & Tomáš Paus & Zdenka Pausova, 2013. "Clustering of the Metabolic Syndrome Components in Adolescence: Role of Visceral Fat," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-7, December.
    4. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Ravikanth Nanduri & Takashi Furusawa & Alexei Lobanov & Bing He & Carol Xie & Kimia Dadkhah & Michael C. Kelly & Oksana Gavrilova & Frank J. Gonzalez & Michael Bustin, 2022. "Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Meiqi Fan & Eun-Kyung Kim & Young-Jin Choi & Yujiao Tang & Sang-Ho Moon, 2019. "The Role of Momordica charantia in Resisting Obesity," IJERPH, MDPI, vol. 16(18), pages 1-17, September.
    7. Hudie Wei & Haolan Wang & Genxin Wang & Lingzhi Qu & Longying Jiang & Shuyan Dai & Xiaojuan Chen & Ye Zhang & Zhuchu Chen & Youjun Li & Ming Guo & Yongheng Chen, 2023. "Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. M. Sinn & L. Riede & J. R. Fleming & D. Funck & H. Lutz & A. Bachmann & O. Mayans & J. S. Hartig, 2024. "Metformin hydrolase is a recently evolved nickel-dependent heteromeric ureohydrolase," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    9. Florian J. Bock & Egor Sedov & Elle Koren & Anna L. Koessinger & Catherine Cloix & Désirée Zerbst & Dimitris Athineos & Jayanthi Anand & Kirsteen J. Campbell & Karen Blyth & Yaron Fuchs & Stephen W. G, 2021. "Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    10. Eryun Zhang & Lihua Jin & Yangmeng Wang & Jui Tu & Ruirong Zheng & Lili Ding & Zhipeng Fang & Mingjie Fan & Ismail Al-Abdullah & Rama Natarajan & Ke Ma & Zhengtao Wang & Arthur D. Riggs & Sarah C. Shu, 2022. "Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    11. Alessandra Dall’Agnese & Jesse M. Platt & Ming M. Zheng & Max Friesen & Giuseppe Dall’Agnese & Alyssa M. Blaise & Jessica B. Spinelli & Jonathan E. Henninger & Erin N. Tevonian & Nancy M. Hannett & Ch, 2022. "The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    12. Laura Czech & Christopher-Nils Mais & Hanna Kratzat & Pinku Sarmah & Pietro Giammarinaro & Sven-Andreas Freibert & Hanna Folke Esser & Joanna Musial & Otto Berninghausen & Wieland Steinchen & Roland B, 2022. "Inhibition of SRP-dependent protein secretion by the bacterial alarmone (p)ppGpp," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. Ziping Niu & Chen Chen & Siyu Wang & Congcong Lu & Zhiyue Wu & Aiyuan Wang & Jing Mo & Jianji Zhang & Yanpu Han & Ye Yuan & Yingao Zhang & Yong Zang & Chaoran He & Xue Bai & Shanshan Tian & Guijin Zha, 2024. "HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Jiang Ren & Shuai Wang & Zhi Zong & Ting Pan & Sijia Liu & Wei Mao & Huizhe Huang & Xiaohua Yan & Bing Yang & Xin He & Fangfang Zhou & Long Zhang, 2024. "TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    15. Naijun Miao & Zhuning Wang & Qinlan Wang & Hongyan Xie & Ninghao Yang & Yanzhe Wang & Jin Wang & Haixia Kang & Wenjuan Bai & Yuanyuan Wang & Rui He & Kepeng Yan & Yang Wang & Qiongyi Hu & Zhaoyuan Liu, 2023. "Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    16. Gregory Alexander Raciti & Francesca Fiory & Michele Campitelli & Antonella Desiderio & Rosa Spinelli & Michele Longo & Cecilia Nigro & Giacomo Pepe & Eduardo Sommella & Pietro Campiglia & Pietro Form, 2018. "Citrus aurantium L. dry extracts promote C/ebpβ expression and improve adipocyte differentiation in 3T3-L1 cells," PLOS ONE, Public Library of Science, vol. 13(3), pages 1-20, March.
    17. Cheng Peng & Yuanna Cheng & Mingtong Ma & Qiu Chen & Yongjia Duan & Shanshan Liu & Hongyu Cheng & Hua Yang & Jingping Huang & Wenyi Bu & Chenyue Shi & Xiangyang Wu & Jianxia Chen & Ruijuan Zheng & Zho, 2024. "Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    18. Fengwei Li & Junjie Liu & Chao Liu & Ziyan Liu & Xiangda Peng & Yinyue Huang & Xiaoyu Chen & Xiangnan Sun & Sen Wang & Wei Chen & Dan Xiong & Xiaotong Diao & Sheng Wang & Jingjing Zhuang & Chuanliu Wu, 2024. "Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Yuan Lin & Theresa A. Ramelot & Simge Senyuz & Attila Gursoy & Hyunbum Jang & Ruth Nussinov & Ozlem Keskin & Yi Zheng, 2024. "Tumor-derived RHOA mutants interact with effectors in the GDP-bound state," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26638-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.