Progranulin attenuates liver fibrosis by downregulating the inflammatory response

Wonbeak Yoo,Seokho Kim,Ki-Sun Kwon,Jaemin Lee,Cheolju Lee,Mohammad Humayun Kabir,Ji-Su Kim,Sangmin Lee,Dongmin Park,Kyung Hee Noh,Dana Jung

doi:10.1038/s41419-019-1994-2

Abstract

Progranulin (PGRN) is a cysteine-rich secreted protein expressed in endothelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being implicated in tissue remodeling, development, inflammation, and protein homeostasis. However, these findings are controversial, and the role of PGRN in liver disease remains unknown. In the current study, we examined the effect of PGRN in two different models of chronic liver disease, methionine‐choline‐deficient diet (MCD)-induced non-alcoholic steatohepatitis (NASH) and carbon tetrachloride (CCl4)-induced liver fibrosis. To induce long-term expression of PGRN, PGRN-expressing adenovirus was delivered via injection into the tibialis anterior. In the CCl4-induced fibrosis model, PGRN showed protective effects against hepatic injury, inflammation, and fibrosis via inhibition of nuclear transcription factor kappa B (NF-κB) phosphorylation. PGRN also decreased lipid accumulation and inhibited pro-inflammatory cytokine production and fibrosis in the MCD-induced NASH model. In vitro treatment of primary macrophages and Raw 264.7 cells with conditioned media from hepatocytes pre-treated with PGRN prior to stimulation with tumor necrosis factor (TNF)-α or palmitate decreased their expression of pro-inflammatory genes. Furthermore, PGRN suppressed inflammatory and fibrotic gene expression in a cell culture model of hepatocyte injury and primary stellate cell activation. These observations increase our understanding of the role of PGRN in liver injury and suggest PGRN delivery as a potential therapeutic strategy in chronic inflammatory liver disease.

Highlights

Liver fibrosis is a response to liver injury due to a variety of causes, including hepatitis infection, excess alcohol consumption, and metabolic disorders
We demonstrate that PGRN administration protects against liver fibrosis and non-alcoholic steatohepatitis by reducing macrophage activation and collagen accumulation
To investigate the role of PGRN in the pathogenesis of liver fibrosis, liver injury was induced by repeated intraperitoneal injection of CCl4, and wild-type mice were administered a control or PGRN-expressing adenovirus for 4 weeks (Fig. 1a)

Summary

Introduction

Liver fibrosis is a response to liver injury due to a variety of causes, including hepatitis infection, excess alcohol consumption, and metabolic disorders. When the injury is sustained, damaged hepatocytes release factors that activate hepatic stellate cells, resulting in excessive extracellular matrix (ECM) production by hepatic stellate cells and non-parenchymal cells[1,2]. This process may result in cirrhosis, the late stage of progressive fibrosis, which is Progranulin (PGRN), which is characterized by repeats of a cysteine-rich granulin motif, is a secretory glycoprotein expressed by a wide variety of cell types in the blood and cerebrospinal fluid[3]. PGRN has been shown to have pleiotropic effects in tissue development, regeneration, inflammation, metabolic disease, and neurodegeneration[4,5,6,7]. PGRN has a protective effect in neurogenerative disease[11,12], while PGRN deficiency inhibits insulin

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