IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56696-y.html
   My bibliography  Save this article

Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis

Author

Listed:
  • Qingwen Zhao

    (Fudan University
    Westlake University)

  • Xuan Cui

    (Fudan University)

  • Qi Zhu

    (Fudan University)

  • Feiyan Li

    (Fudan University)

  • Ran Bao

    (Dandong Central Hospital)

  • Ting Shi

    (Fudan University)

  • Haojie Liu

    (Fudan University)

  • Wenjing Lv

    (Fudan University)

  • Yingjiang Xu

    (Binzhou Medical University Hospital)

  • Yue Gao

    (Westlake University)

  • Qi-Qun Tang

    (Fudan University)

  • Min Zhang

    (Qingpu Branch of Zhongshan Hospital affiliated to Fudan University)

  • Dongning Pan

    (Fudan University
    Qingpu Branch of Zhongshan Hospital affiliated to Fudan University)

Abstract

Lysine methyltransferase KMT5C catalyzes deposition of trimethylation on histone H4 lysine 20 (H4K20me3), an epigenetic marker usually associated with gene repression and maintenance of heterochromatin. KMT5C is widely expressed in a variety of tissues, however, its functional role in liver has not been explored. Here, we show Kmt5c is a fasting- and glucagon-induced gene in liver which regulates hepatic gluconeogenesis. Loss of KMT5C in hepatocytes results in downregulated gluconeogenic gene expression and compromised glucose output during fasting. KMT5C fosters gluconeogenesis through decreasing ubiquitination-mediated PGC-1α degradation, which is unexpectedly independent of its methyltransferase activity. In fact, KMT5C impedes the E3 ligase RNF34 binding to the C-terminal of PGC-1α and subsequent ubiquitination-associated degradation. The diabetic mice models and patients show elevated KMT5C levels in the livers, and KMT5C knockdown beneficially reduces gluconeogenesis and fasting blood glucose levels. In conclusion, the present study identifies KMT5C as a hepatic gluconeogenesis regulator by affecting PGC-1α stability.

Suggested Citation

  • Qingwen Zhao & Xuan Cui & Qi Zhu & Feiyan Li & Ran Bao & Ting Shi & Haojie Liu & Wenjing Lv & Yingjiang Xu & Yue Gao & Qi-Qun Tang & Min Zhang & Dongning Pan, 2025. "Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56696-y
    DOI: 10.1038/s41467-025-56696-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56696-y
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-56696-y?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. Stephan Herzig & Fanxin Long & Ulupi S. Jhala & Susan Hedrick & Rebecca Quinn & Anton Bauer & Dorothea Rudolph & Gunther Schutz & Cliff Yoon & Pere Puigserver & Bruce Spiegelman & Marc Montminy, 2001. "Correction: CREB regulates hepatic gluconeogenesis through the coactivator PGC-1," Nature, Nature, vol. 413(6856), pages 652-652, October.
    2. Stephan Herzig & Fanxin Long & Ulupi S. Jhala & Susan Hedrick & Rebecca Quinn & Anton Bauer & Dorothea Rudolph & Gunther Schutz & Cliff Yoon & Pere Puigserver & Bruce Spiegelman & Marc Montminy, 2001. "CREB regulates hepatic gluconeogenesis through the coactivator PGC-1," Nature, Nature, vol. 413(6852), pages 179-183, September.
    3. Pere Puigserver & James Rhee & Jerry Donovan & Christopher J. Walkey & J. Cliff Yoon & Francesco Oriente & Yukari Kitamura & Jennifer Altomonte & Hengjiang Dong & Domenico Accili & Bruce M. Spiegelman, 2003. "Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction," Nature, Nature, vol. 423(6939), pages 550-555, May.
    4. Seung-Hoi Koo & Lawrence Flechner & Ling Qi & Xinmin Zhang & Robert A. Screaton & Shawn Jeffries & Susan Hedrick & Wu Xu & Fayçal Boussouar & Paul Brindle & Hiroshi Takemori & Marc Montminy, 2005. "The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism," Nature, Nature, vol. 437(7062), pages 1109-1114, October.
    Full references (including those not matched with items on IDEAS)

    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. Ewa Bielczyk-Maczynska & Meng Zhao & Peter-James H. Zushin & Theresia M. Schnurr & Hyun-Jung Kim & Jiehan Li & Pratima Nallagatla & Panjamaporn Sangwung & Chong Y. Park & Cameron Cornn & Andreas Stahl, 2022. "G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Storm N. S. Reid & Joung-Hyun Park & Yunsook Kim & Yi Sub Kwak & Byeong Hwan Jeon, 2020. "In Vitro and In Vivo Effects of Fermented Oyster-Derived Lactate on Exercise Endurance Indicators in Mice," IJERPH, MDPI, vol. 17(23), pages 1-17, November.
    3. Yue Liu & Yue Yang & Chenying Xu & Jianxing Liu & Jiale Chen & Guoqing Li & Bin Huang & Yi Pan & Yanfeng Zhang & Qiong Wei & Stephen J. Pandol & Fangfang Zhang & Ling Li & Liang Jin, 2023. "Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Yuta Ozaki & Koji Ohashi & Naoya Otaka & Hiroshi Kawanishi & Tomonobu Takikawa & Lixin Fang & Kunihiko Takahara & Minako Tatsumi & Sohta Ishihama & Mikito Takefuji & Katsuhiro Kato & Yuuki Shimizu & Y, 2023. "Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Simeon R. Mihaylov & Lydia M. Castelli & Ya-Hui Lin & Aytac Gül & Nikita Soni & Christopher Hastings & Helen R. Flynn & Oana Păun & Mark J. Dickman & Ambrosius P. Snijders & Robert Goldstone & Oliver, 2023. "The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    6. Pengfei Xu & Yingjie Zhang & Xinghao Jiang & Junyan Li & Liying Song & Mir Hasson Khoso & Yunye Liu & Qiang Wu & Guiping Ren & Deshan Li, 2016. "Canine Fibroblast Growth Factor 21 Ameliorates Hyperglycemia Associated with Inhibiting Hepatic Gluconeogenesis and Improving Pancreatic Beta-Cell Survival in Diabetic Mice and Dogs," PLOS ONE, Public Library of Science, vol. 11(5), pages 1-19, May.
    7. Huanqing Gao & Liang Zhou & Yiming Zhong & Zhen Ding & Sixiong Lin & Xiaoting Hou & Xiaoqian Zhou & Jie Shao & Fan Yang & Xuenong Zou & Huiling Cao & Guozhi Xiao, 2022. "Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. André A. Weber & Xiaojing Yang & Elvira Mennillo & Jeffrey Ding & Jeramie D. Watrous & Mohit Jain & Shujuan Chen & Michael Karin & Robert H. Tukey, 2022. "Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice," Nature Communications, Nature, vol. 13(1), pages 1-13, 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:16:y:2025:i:1:d:10.1038_s41467-025-56696-y. 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.