Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice.
Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice.
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Kindlin-2 单倍体不足通过靶向 Foxo1 预防小鼠脂肪肝
DOI：
10.1038/s41467-022-28692-z
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发表时间：
2022-02-23
影响因子：
16.6
通讯作者：
Xiao G
中科院分区：
文献类型：
--
作者：
Gao H;Zhou L;Zhong Y;Ding Z;Lin S;Hou X;Zhou X;Shao J;Yang F;Zou X;Cao H;Xiao G
非酒精性脂肪性肝病（NAFLD）影响大量人群，其机制尚未完全确定。在这里，我们报告Kindlin-2在肥胖小鼠和NAFLD患者的肝脏中显著上调。肝细胞中Kindlin-2单倍不足可改善高脂饮食（HFD）诱导的NAFLD和葡萄糖耐受不良，而不影响小鼠的能量代谢。相反，Kindlin-2在肝脏中的过表达加重了NAFLD，并促进了肝细胞中的脂质代谢紊乱和炎症。Kindlin-2的C-末端区域（aa 570-680）通过抑制Foxo 1的泛素化和Skp 2 E3连接酶的降解来结合Foxo 1并稳定Foxo 1。Kindlin-2缺陷增加Foxo 1在Ser 256的磷酸化，这有利于Skp 2的泛素化。因此，Kindlin-2缺失下调肝细胞中的Foxo 1蛋白。肝脏中Foxo 1过表达消除Kindlin-2单倍不足对小鼠NAFLD的改善作用最后，AAV 8介导的Kindlin-2在肝脏中的shRNA敲低使肥胖小鼠的NAFLD恶化。总的来说，我们证明Kindlin-2不足通过促进Foxo 1降解来预防脂肪肝。
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.
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DOI：
10.3791/56993
发表时间：
2018-02-12
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Cabral F;Miller CM;Kudrna KM;Hass BE;Daubendiek JG;Kellar BM;Harris EN
通讯作者：
Harris EN
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
影响因子：
24.5
作者：
Dufour, Jean-Francois;Caussy, Cyrielle;Loomba, Rohit
通讯作者：
Loomba, Rohit
胰源性因子促进小鼠肝脏脂肪生成：Forkhead Box 1 信号通路的作用
影响因子：
13.5
作者：
Li, Jing;Chi, Yujing;Guan, Youfei
通讯作者：
Guan, Youfei
焦点粘附蛋白 Kindlin-2 调节小鼠骨稳态
影响因子：
12.7
作者：
Cao, Huiling;Yan, Qinnan;Xiao, Guozhi
通讯作者：
Xiao, Guozhi