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

Huanqing Gao, Liang Zhou, Yiming Zhong, Zhen Ding, Sixiong Lin, Xiaoting Hou, Xiaoqian Zhou, Jie Shao, Fan Yang, Xuenong Zou, Huiling Cao () and Guozhi Xiao ()
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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
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

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28692-z

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