4.7 Article

Serpina3c deficiency induced necroptosis promotes non-alcoholic fatty liver disease through β-catenin/Foxo1/TLR4 signaling

期刊

FASEB JOURNAL
卷 36, 期 5, 页码 -

出版社

WILEY
DOI: 10.1096/fj.202101345RRR

关键词

-

资金

  1. National Natural Science Foundation of China (NSFC) [81770452]

向作者/读者索取更多资源

This study reveals that serpina3c modulates the development of NAFLD by inhibiting necroptosis via the beta-catenin/Foxo1/TLR4 pathway, highlighting a novel mechanism for the progression of NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is a public health challenge and an increasing cause of chronic liver disease worldwide. However, the underlying molecular mechanism remains unclear. The aim of this study was to determine the precise role of serpina3c in the process of NAFLD. Male Apoe(-/-)/serpina3c(-/-) double knockout (DKO) and Apoe(-/-) mice were fed a high-fat diet (HFD) for 12 weeks. Several markers of steatosis and inflammation were evaluated. In vitro cell models induced by palmitic acid (PA) treatment were used to evaluate the beneficial effect of serpina3c on necroptosis and the underlying molecular mechanism. Compared with Apoe(-/-) mice, DKO mice exhibited a significantly exacerbated hepatic steatosis, increased hepatic triglyceride content and expression of genes involved in lipid metabolism (SREBP1c and SCD1), promoted hepatic inflammation and fibrosis, promoted necroptosis by increasing expression of receptor-interacting protein 3 (RIP3), phosphorylated mixed lineage kinase domain-like (MLKL) and high mobility group box 1 (HMGB1). Notably, serpina3c deficiency increased beta-catenin, Foxo1, and Toll-like receptor 4 (TLR4) protein expression. In vitro , serpina3c knockdown promoted necroptosis and lipid droplet formation under condition of lipotoxicity. However, these phenomena were reversed by the overexpression of serpina3c. Mechanistically, downregulation of serpina3c expression promoted Foxo1 and beta-catenin colocalized in the nucleus under condition of lipotoxicity, consequently upregulating the expression of TLR4. Conversely, disruption of Foxo1-beta/catenin by Foxo1 and beta-catenin inhibitors decreased TLR4 expression and ameliorated hepatic necroptosis in vitro. This study highlights a novel mechanism that serpina3c modulates NAFLD development by inhibiting necroptosis via beta-catenin/Foxo1/TLR4.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据