The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis

Abstract

Chronic liver injury can be caused by many factors, including virus infection, alcohol intake, cholestasis and abnormal fat accumulation. Nonalcoholic steatohepatitis (NASH) has become the main cause of liver fibrosis worldwide. Recently, more and more evidences show that hepatic microenvironment is involved in the pathophysiological process of liver fibrosis induced by NASH. Hepatic microenvironment consists of various types of cells and intercellular crosstalk among different cells in the liver sinusoids. Liver sinusoidal endothelial cells (LSECs), as the gatekeeper of liver microenvironment, play an irreplaceable role in the homeostasis and alterations of liver microenvironment. Many recent studies have reported that during the progression of NASH to liver fibrosis, LSECs are involved in various stages mediated by a series of mechanisms. Therefore, here we review the key role of crosstalk between LSECs and hepatic microenvironment in the progression of NASH to liver fibrosis (steatosis, inflammation, and fibrosis), as well as promising therapeutic strategies targeting LSECs.

Keywords: cross talk; liver fibrosis; liver sinusoidal endothelial cells; nonalcoholic steatohepatitis - NASH; targeted therapy.

Figure 1

Structure of liver sinusoidal microenvironment. As the gatekeeper of hepatic sinusoidal microenvironment, LSECs constitute the interface between the sinusoid and blood flow. The intercellular crosstalk between LSECs and various cells including hepatocytes, lymphocytes, neutrophils, macrophages, and hepatic stellate cells, which together consist of the hepatic microenvironment.

Figure 2

Sinusoidal crosstalk mediated by LSECs play a key role in progression of NASH to liver fibrosis. A series of pathophysiological processes from NASH to liver fibrosis are mediated by LSECs. Capillarization and dysfunction of LSECs appear in early stage of NASH. Capillarized LSECs acquire a pro-inflammatory phenotype, recruiting immune cells including neutrophils, monocytes and lymphocytes to the hepatic microenvironment, promoting HCs steatosis and cell death, activating HSCs and KCs, and promoting liver fibrosis.