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Updated: Oct 2, 2025
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice
Huanqing Gao1, Liang Zhou2, Yiming Zhong1
1Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
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.
Insights
Kindlin-2 protein promotes nonalcoholic fatty liver disease (NAFLD). Reducing Kindlin-2 levels protects against fatty liver by enhancing the degradation of Foxo1, a key protein in liver metabolism.
Area of Science:
- Hepatology
- Molecular Biology
- Metabolic Diseases
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition with unclear underlying mechanisms.
- Kindlin-2 is significantly upregulated in the livers of obese mice and human NAFLD patients.
Purpose of the Study:
- To investigate the role of Kindlin-2 in the pathogenesis of NAFLD.
- To elucidate the molecular mechanism by which Kindlin-2 influences NAFLD progression.
Main Methods:
- Utilized mouse models with Kindlin-2 haploinsufficiency and overexpression.
- Employed high-fat diet (HFD) induction for NAFLD models.
- Investigated protein-protein interactions and degradation pathways involving Kindlin-2 and Foxo1.
- Used AAV8-mediated shRNA for in vivo knockdown of Kindlin-2.
Main Results:
- Kindlin-2 haploinsufficiency ameliorated HFD-induced NAFLD and glucose intolerance in mice.
- Kindlin-2 overexpression exacerbated NAFLD, promoting lipid disorder and inflammation.
- Kindlin-2 binds to and stabilizes Foxo1, inhibiting its Skp2-mediated degradation.
- Kindlin-2 deficiency led to increased Foxo1 phosphorylation and degradation.
- Foxo1 overexpression reversed the protective effects of Kindlin-2 deficiency on NAFLD.
- Kindlin-2 knockdown alleviated NAFLD in obese mice.
Conclusions:
- Kindlin-2 plays a crucial role in promoting NAFLD pathogenesis.
- Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation.
- Targeting Kindlin-2 may offer a therapeutic strategy for NAFLD.
