Abstract
Efforts have been made in the prevention and treatment of liver fibrosis. The inhibition or depletion of the hepatic stellate cells (HSCs) has been considered as a potential approach. Recently, there are numbers of studies about the role of the circular RNA in the disease progression. However, the role of circular RNA in the regulation of HSCs and the progression of liver fibrosis remained elusive. In this study, we constructed a CCl4-induced liver fibrosis mouse model and overexpressed hsa_circ_0004018 in HSCs. Then, salvianolic acid B was used to treat HSCs in vitro. We found that hsa_circ_0004018 is downregulated in liver fibrogenesis. Luciferase reporter assay was performed to verify the interaction of hsa_circ_0004018, hsa-miR-660-3p and TEP1. It showed that hsa_circ_0004018 may act as a sponge of hsa-miR-660-3p, which can target and downregulate the expression of TEP1. hsa_circ_0004018 expressing lentivirus was used to investigate the in-vivo function of hsa_circ_0004018 in CCl4-induced liver fibrosis mice. We also reveal that the hsa_circ_0004018/hsa-miR-660-3p/TEP1 axis contributes to the proliferation and activation of HSCs. In addition, the overexpression of hsa_circ_0004018 alleviated the progression of liver fibrosis. In conclusion, our study highlights hsa_circ_0004018 as a potential biomarker and therapeutic target for liver fibrosis.
Highlights
Liver fibrosis is a common feature of chronic liver injury caused by viral hepatitis, metabolic disorder, autoimmune conditions and other reasons [1]
The quiescent hepatic stellate cells (HSCs) would be activated by the cytokines, such as interleukin-6 (IL-6) [5, 6], interleukin-17 (IL-17) [7,8,9] and interleukein-22 (IL-22) [8, 9], secreted from the neighboring cell types within the injured liver microenvironment, including Kupffer cells, hepatocytes, sinusoidal endothelial cells, leukocytes, et cetera [6]
The low expression of hsa_circ_0004018 especially in HSCs was associated with the poor progression of liver fibrosis in mouse model
Summary
Liver fibrosis is a common feature of chronic liver injury caused by viral hepatitis, metabolic disorder, autoimmune conditions and other reasons [1]. It represents an early stage of liver cirrhosis which may develop into liver failure or liver cancer especially hepatocellular carcinoma [2]. The quiescent HSCs would be activated by the cytokines, such as interleukin-6 (IL-6) [5, 6], interleukin-17 (IL-17) [7,8,9] and interleukein-22 (IL-22) [8, 9], secreted from the neighboring cell types within the injured liver microenvironment, including Kupffer cells, hepatocytes, sinusoidal endothelial cells, leukocytes, et cetera [6]. As the HSCs account for 80% of total type I collagen (COL1A1) in the fibrotic liver, the HSCs inhibition with drugs like www.aging-us.com salvianolic acid B (Sal B) is always considered as a potential therapy for liver fibrosis [2, 10, 11]
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