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

Abstract

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 β‐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 β‐catenin colocalized in the nucleus under condition of lipotoxicity, consequently upregulating the expression of TLR4. Conversely, disruption of Foxo1‐β/catenin by Foxo1 and β‐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 β‐catenin/Foxo1/TLR4.

Directing Cell Delivery to Murine Atherosclerotic Aortic Lesions via Targeting Inflamed Circulatory Interface using Nanocarriers

“…In addition to NAFLD-induced hepatic inflammation, partial deposition of MSCs in liver could also be ascribed to hepatic clearance, which is known to occur in other MSC therapies. 1,39 Compared to biodistribution in hepatic tissue, we observed similar amounts of MSA-nanocarrier-coated MSCs present in the surrounding area of hepatic vessels/sinusoids. This may suggest that deposition of MSCs in liver can be due to a general indiscriminate clearance of MSC therapy from the body.…”

To explore the pathogenesis and scientific connotation of non‐alcoholic fatty liver based on the theory of turbid toxin of traditional Chinese medicine

“…In animal studies, TLR4 mRNA, MyD88 mRNA, NF‐κB mRNA, and their proteins were significantly upregulated in rats with high‐fat diet‐induced NAFLD. TLR4 protein expression was also positively correlated with total cholesterol and TG levels [75, 76].…”

The versatile role of Serpina3c in physiological and pathological processes: a review of recent studies

“…Ultimately, hepatocellular carcinoma (HCC) may occur on the basis of cirrhosis ( 74 , 75 ). Some studies have shown that compared with Apoe knockout group, Apoe and Serpina3c double knockout significantly promoted liver steatosis in HFD-fed mice, which further led to liver inflammation and liver fibrosis, and significantly aggravated liver injury ( 76 ). They found that Seprina3c deficiency also increased the expression of genes related to lipogenesis ( Srebf1 and Scd1 ) in the livers of HFD-fed mice, suggesting that Serpina3c may block the development of NAFLD.…”

“…Serpina3c knockout promoted the expression of RIPK3 and p-MLKL in mouse liver. In vitro , Serpina3c inhibited palmitic acid (PA)-induced necroptosis ( 76 ), suggesting that Serpina3c can inhibit necroptosis under lipotoxic conditions, while Serpina3c deficiency increased the sensitivity of the liver to lipotoxicity and promoted necroptosis. Previous studies have shown that Toll-like receptor 4 (TLR4) can regulate necroptosis ( 83 , 84 ).…”

“…It has been shown that Serpina3c can inhibit the Wnt/β-catenin signal pathway and keep the intracellular β-catenin at a low level. The lack of Serpina3c makes the activated β-catenin enter the nucleus to bind to Foxo1 and activate it, and the activated Foxo1 increases the transcription of TLR4 ( 76 ). Therefore, as a Wnt inhibitor, Serpina3c can inhibit hepatocyte necroptosis by blunting the β-catenin/Foxo1/TLR4 pathway, which ameliorates NAFLD ( Figure 5 ).…”