期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28692-z
关键词
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资金
- National Key Research and Development Program of China [2019YFA0906004, 2019YFA0906001]
- National Natural Science Foundation of China [81991513, 82022047, 81630066, 81870532, 81972100]
- Guangdong Provincial Science and Technology Innovation Council [2017B030301018]
- Shenzhen Municipal Science and Technology Innovation Council [JCYJ20180302174117738, JCYJ20180302174246105, KQJSCX20180319114434843]
Increased expression of Kindlin-2 in patients with nonalcoholic fatty liver disease (NAFLD) and obese mice. Haploinsufficiency of Kindlin-2 in hepatocytes ameliorates NAFLD, while overexpression exacerbates it, by modulating Foxo1 in hepatocytes.
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. Here, the authors show that expression of kindlin-2 is increased in patients with nonalcoholic fatty liver disease (NAFLD). In mouse models, specific deletion of kindlin-2 in liver ameliorates, while its overexpression exacerbates, NAFLD by modulating Foxo1 in hepatocytes.
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