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Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice

Author

Listed:
  • Huanqing Gao

    (Southern University of Science and Technology)

  • Liang Zhou

    (Shenzhen University Health Science Center)

  • Yiming Zhong

    (Southern University of Science and Technology)

  • Zhen Ding

    (Southern University of Science and Technology)

  • Sixiong Lin

    (Southern University of Science and Technology
    The First Affiliated Hospital of Sun Yat-sen University)

  • Xiaoting Hou

    (Southern University of Science and Technology)

  • Xiaoqian Zhou

    (The First People’s Hospital of Guiyang)

  • Jie Shao

    (Chinese Academy of Sciences (CAS))

  • Fan Yang

    (Chinese Academy of Sciences (CAS))

  • Xuenong Zou

    (The First Affiliated Hospital of Sun Yat-sen University)

  • Huiling Cao

    (Southern University of Science and Technology)

  • Guozhi Xiao

    (Southern University of Science and Technology)

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28692-z
    DOI: 10.1038/s41467-022-28692-z
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    References listed on IDEAS

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    1. 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.
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