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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s)
As an initial step to investigate whether Kindlin-2 plays a role in the pathogenesis of NAFLD, we determined its expression in livers from high-fat diet (HFD)-fed mice, db/db mice, which are obese and diabetic due to mutation in the gene encoding the leptin receptor, and ob/ob mice, which harbor a mutation in the gene encoding leptin and are obese and diabetic
Expression of the Kindlin-2 and fatty acid synthase (Fas) mRNA and that of Kindlin-2 protein were all significantly upregulated in livers of patients with NAFLD compared to those in liver samples from nonsteatotic donors (ND), as revealed by western blotting, quantitative real-time polymerase chain reaction analysis and IHC staining (Fig. 1k–n)
Summary
Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. Foxo[1] overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. We demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo[1] degradation. We utilize gain- and loss-of-function approaches to determine whether and how Kindlin-2 is involved in the progression of high-fat diet (HFD)-induced hepatic steatosis by investigating the effects of Kindlin-2 loss and overexpression in hepatocytes on the development of fatty liver in mice. We demonstrate that Kindlin-2 insufficiency in hepatocytes provides dramatic protection against fatty liver in HFD-fed mice and ob/ob mice. Kindlin-2 insufficiency exerts such a protective function by promoting the Skp2-dependent ubiquitination and proteasomal degradation of transcription factor Foxo[1]
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