S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression

Abstract

Introduction: Liver fibrosis caused by hepatic stellate cells (HSCs) activation is implicated in the pathogenesis of liver diseases. To date, there has been no effective intervention means for this process. S100 proteins are calcium-binding proteins that regulate cell growth and differentiation. This study aimed to investigate whether S100A16 induces HSCs activation and participates in liver fibrosis progression.

Methods: HSCs were isolated, and the relationship between S100A16 expression and HSCs activation was studied. S100a16 knockdown and transgenic mice were generated and subjected to HSCs activation and liver fibrosis stimulated by different models. Clinical samples were collected for further confirmation. Alterations in gene expression in HSCs were investigated, using transcriptome sequencing to determine the underlying mechanisms.

Results: We observed increased S100A16 levels during HSCs activation. Genetic silencing of S100a16 prevented HSCs activation in vitro. Furthermore, S100a16 silencing exhibited obvious protective effects against HSCs activation and fibrosis progression in mice. In contrast, S100a16 transgenic mice exhibited spontaneous liver fibrosis. S100A16 was also upregulated in the HSCs of patients with fibrotic liver diseases. RNA sequencing revealed that C-X-C motif chemokine receptor 4 (Cxcr4) gene was a crucial regulator of S100A16 induction during HSCs activation. Mechanistically, S100A16 bound to P53 to induce its degradation; this augmented CXCR4 expression to activate ERK 1/2 and AKT signaling, which then promoted HSCs activation and liver fibrosis.

Conclusions: These data indicate that S100a16 deficiency prevents liver fibrosis by inhibiting Cxcr4 expression. Targeting S100A16 may provide insight into the pathogenesis of liver fibrosis and pave way for the design of novel clinical therapeutic strategies.

Keywords: C-X-C motif chemokine receptor 4; Hepatic stellate cells activation; Liver fibrosis; S100A16.