Salidroside Inhibits CCl4-Induced Liver Fibrosis in Mice by Reducing Activation and Migration of HSC Induced by Liver Sinusoidal Endothelial Cell-Derived Exosomal SphK1

Abstract

Sphingosine kinase 1 (SphK1)/Sphingosine-1-phosphate (S1P)/S1PRs signaling pathway is known to involve the advancement of liver fibrosis. Exosomal SphK1 promotes hepatic stellate cells (HSC) migration. Salidroside (Sal) inhibits liver fibrosis, but its mechanism is yet to be elucidated. This study was to explore the influences of Sal on the SphK/S1P/S1PRs signaling pathway in liver fibrosis induced by carbon tetrachloride (CCl4) in vivo, and investigated the mechanism of Sal affecting the migration and activation of HSC triggered by exosomal SphK1 in vitro. Our data showed that Sal reduced the activities of alanine transaminase (ALT), aspartate aminotransferase (AST) in serum, and hydroxyproline (Hyp) content in the liver tissue. Sal subdued the expression of α-smooth muscle actin (α-SMA), fibronectin (FN) and type I collagen (Col I) of the liver. Sal also reduced mitochondria-induced hepatocyte apoptosis and to inhibit JNK activation. Furthermore, Sal remarkably eradicated the influence of SphK1, SphK2, S1P, and S1PRs triggered by CCl4, whether stimulating or hindering. Compared with serum-derived exosomes from model group mice, serum-derived exosomes from Sal group mice expressed lower SphK1 and reduced JS 1 (mouse HSC cell line) migration. In addition, Sal was also observed to subdue Col I expression, AKT activation, and LX-2 migration induced by exosomal SphK1 from SK-HEP-1 (a kind of liver sinusoidal endothelial cells (LSEC) cell line). In conclusion, Sal could effectively alleviate liver injury, hepatocyte apoptosis, and liver fibrosis in vivo, providing supports that the protective effects of Sal might be realized by suppressing JNK activation and modulating the SphK/S1P/S1PRs axis. In vitro, it was observed that Sal might alleviate LX-2 migration and activation induced by exosomal SphK1 by inhibiting the AKT activation.

Liver fibrosis: Extracellular vesicles mediated intercellular communication in perisinusoidal space

“…Clinically, high concentrations of SK‐1 expressing exosomes are measured in patients with cirrhosis. [ 69 ] The different intercellular communication pathways of EVs in the perisinusoidal space are summarized in Figure 3.…”

When healing turns into killing – the pathophysiology of pancreatic and hepatic fibrosis

“…The above traits also well describe the fibroblast type of cells primarily attributed to liver and pancreatic fibrosis: hepatic and pancreatic stellate cells (HSCs and PSCs). HSCs constitute 5–8% of all hepatic cells and form perisinusoidal populations in the space of Disse (Lee & Friedman, 2020; Li et al., 2008; Ye et al., 2021). These cells were first identified in 1952 by Toshio Ito and are often referred to as Ito cells (Ito & Nemoto, 1952).…”

The Role of Extracellular Vesicles in Liver Pathogenesis

“…20 Cholangiocyte-derived exosomes are usually with specific marker of cytokeratin 19. 19 Sphingosine kinase 1 is found in exosomes isolated from liver sinusoidal endothelial cell line, SK-HEP-1, 21 whereas connective tissue growth factor (CTGF/CCN2) is found in exosomes from highly activated mouse HSCs. 22 Liver cells can be both the donor and the recipient of EVs, resulting in a multiway communication network among the various cells in the liver.…”