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Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice

Author

Listed:
  • Xue Yang

    (Rutgers University)

  • Jianming Wang

    (Rutgers University)

  • Chun-Yuan Chang

    (Rutgers University)

  • Fan Zhou

    (Rutgers University)

  • Juan Liu

    (Rutgers University)

  • Huiting Xu

    (Rutgers-Robert Wood Johnson Medical School)

  • Maria Ibrahim

    (Rutgers University)

  • Maria Gomez

    (Rutgers University)

  • Grace L. Guo

    (Rutgers University
    Rutgers University
    Department of Veterans Affairs New Jersey Health Care System)

  • Hao Liu

    (Rutgers School of Public Health
    Rutgers University)

  • Wei-Xing Zong

    (Rutgers University
    Rutgers University)

  • Fredric E. Wondisford

    (Rutgers-Robert Wood Johnson Medical School)

  • Xiaoyang Su

    (Rutgers-Robert Wood Johnson Medical School
    Rutgers Cancer Institute of New Jersey)

  • Eileen White

    (Rutgers University
    Princeton University)

  • Zhaohui Feng

    (Rutgers University)

  • Wenwei Hu

    (Rutgers University)

Abstract

Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.

Suggested Citation

  • Xue Yang & Jianming Wang & Chun-Yuan Chang & Fan Zhou & Juan Liu & Huiting Xu & Maria Ibrahim & Maria Gomez & Grace L. Guo & Hao Liu & Wei-Xing Zong & Fredric E. Wondisford & Xiaoyang Su & Eileen Whit, 2024. "Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44924-w
    DOI: 10.1038/s41467-024-44924-w
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    References listed on IDEAS

    as
    1. Yu Shi & Weina Gao & Nikki K. Lytle & Peiwu Huang & Xiao Yuan & Amanda M. Dann & Maya Ridinger-Saison & Kathleen E. DelGiorno & Corina E. Antal & Gaoyang Liang & Annette R. Atkins & Galina Erikson & H, 2019. "Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring," Nature, Nature, vol. 569(7754), pages 131-135, May.
    2. Shao-Wei Lu & Hong-Chin Pan & Yu-Hsiang Hsu & Kung-Chao Chang & Li-Wha Wu & Wei-Yu Chen & Ming-Shi Chang, 2020. "IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    3. Haiyang Yu & Xuetian Yue & Yuhan Zhao & Xiaoyan Li & Lihua Wu & Cen Zhang & Zhen Liu & Kevin Lin & Zijun Y. Xu-Monette & Ken H. Young & Juan Liu & Zhiyuan Shen & Zhaohui Feng & Wenwei Hu, 2014. "LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
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