Expression of neuropeptide Y is increased in an activated human HSC cell line

Wufei Dai,Yufeng Sun,Yang Liu,Yu Zhang,Yali Zhang,Xiufang Lv,Changjiang Sun

doi:10.1038/s41598-019-45932-3

Abstract

Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian central and peripheral nervous systems. Transgenic mice overexpressing NPY in noradrenergic neurons have increased level of hepatic triglycerides, fatty acids and cholesterol, which contributed to the development of hepatosteatosis. However, the roles of NPY in the activation of hepatic stellate cells (HSCs) and the underlying mechanisms remain unclear. This study aimed to investigate the expression and secretion of NPY in human immortalized HSC LX-2 cells and the regulatory function of NPY on the fibrogenic response in LX-2 cells, to explore the potential association between NPY and LX-2 activation. The results showed an increase in the expression and secretion of NPY(1–36) in activated LX-2 cells. Both endogenous and exogenous NPY(1–36) induced the phosphorylation of mTOR, p70S6K, and 4EBP1 and promoted the fibrogenic response via NPY Y1 receptor subtype (NPY1R), as these responses were blocked by either an NPY1R antagonist (BIBP3226) or NPY1R knockdown. Moreover, NPY(1–36) serum levels were increased in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) and presented a positive relationship with MELD scores in LC patients. These findings suggest that immortalized HSCs LX-2 have the potential to produce NPY(1–36). High serum levels of NPY(1–36) is correlated with hepatic dysfunction in cirrhotic patients.

Highlights

Neuropeptide Y (NPY) is the most abundant neuropeptide in the mammalian central nervous system and plays important roles in feeding behaviours, depression, stress, and hypothalamic hormone release[1]
We further demonstrated via fluorescence microscopy that both LX-2 cells and L-02 cells expressed the NPY Y1 receptor subtype (NPY1R) protein and that it was diffusely spread throughout the cell cytoplasm and nucleus
These results suggest that NPY and NPY1R are expressed in immortalized LX-2 hepatic stellate cells (HSCs)

Summary

Introduction

Neuropeptide Y (NPY) is the most abundant neuropeptide in the mammalian central nervous system and plays important roles in feeding behaviours, depression, stress, and hypothalamic hormone release[1]. Hepatic fibrosis and cirrhosis are the result of multiple types of liver injury caused by various factors, including viruses, metabolic diseases and cholestatic, autoimmune and drug induction[6]. Many studies both in animal models and in humans has shown that fibrogenesis is a dynamic and reversible process[7,8]. HSCs are in contact with a large number of hepatocytes, adjacent sinusoidal endothelial cells, stellate cells, and nerve endings. We sought to investigate human circulating NPY levels and their relationship with the severity of liver cirrhosis

Objectives

Methods

Results

Conclusion