Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells

Ying Wang,Jiayi Song,Xinrui Lv,Weitong Pan,Jiaqi Bo,Hongyan Bian,Shuangyu Lv

doi:10.1007/s11010-019-03581-0

Abstract

Apelin participates in cardiovascular functions, metabolic disease, and homeostasis disorder. However, the biological function of apelin in liver diseases, especially liver fibrosis is still under investigation. The present study aimed to investigate the expression of apelin in nonalcoholic fatty liver disease (NAFLD) and the mechanism of apelin promoting hepatic fibrosis through ERK signaling in hepatic stellate LX-2 cells. The results showed that the ALT and AST levels in serum were increased in the mice fed HFC. The histological staining revealed that hepatocellular steatosis and ballooning degeneration was severe, and fibrogenesis appeared as increased pericellular collagen deposition along with pericentral (lobular) collagen deposition in the mice fed HFC. Immunochemistry and qRT-PCR results showed that the expression of apelin and profibrotic genes was higher as compared to the control group. The in vitro experiments demonstrated that apelin-13 upregulated the transcription and translation levels of collagen type I (collagen-I) and α-smooth muscle actin (α-SMA) in LX-2 cells. The immunofluorescent staining, qRT-PCR, and Western blot results showed that the overexpression of apelin markedly increased the expression of α-SMA and cyclinD1. The LX-2 cells treated with apelin-13 displayed an increased expression of pERK1/2 in a time-dependent manner, while the pretreatment with PD98059 abolished the apelin-induced expression of α-SMA and cyclinD1. Furthermore, the in vivo and in vitro assays suggested a key role of apelin in promoting liver fibrosis, and the underlying mechanism might be ascribed to the apelin expression of profibrotic genes via ERK signaling pathway.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver diseases in adults and children worldwide with a continual increase in the number of incidences [1]
The IHC staining revealed the expression of apelin, APJ, α-smooth muscle actin (α-SMA), and cyclinD1 in the mice of the model group as assessed by qRT-PCR, and the arrow point to specific proteins (Fig. 3a–d). These results indicated that apelin and APJ participated in the hepatic steatosis in NAFLD of mice
NAFLD pathogenesis is associated with inflammation, steatosis, and fibrosis of chronic liver injury [25,26,27]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver diseases in adults and children worldwide with a continual increase in the number of incidences [1]. Irrespective of the cause, liver diseases typically experience three major events, such as hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Apelin is an endogenous ligand for the APJ receptor (angiotensin II receptor-like-1, AT-1). The prepro-apelin consisted of 77 amino acids that could be cleaved into several biologically active forms of peptides, such as apelin-13, -16, -17, and -36. Each isoform harbored a potent activator for APJ. Both apelin-13 and apelin-17 exerted a stronger activity than apelin-36 [6,7,8].

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Methods

Conclusion