Liver fibrosis is a common pathway leading to cirrhosis and liver cancer in chronic liver disease, and has a great influence on the prognosis of the disease. Activated stellate cells, which are induced by various stimuli, overproduce extracellular matrix such as collagen, and play a central role in the development of liver fibrosis.
Prostanoids, consisting of prostaglandins (PGs) and thromboxane, exert a variety of actions in the body by binding to their specific receptors. Previously, we have reported that prostaglandin I₂ suppresses the development of diet-induced nonalcoholic steatohepatitis in mice (FASEB J, 2018.). However, role of prostanoids in the function of hepatic stellate cells remain unclear. Therefore, we examined the role of prostanoids using primary cultured hepatic stellate cells.
RT-qPCR analysis of prostanoid receptor mRNA expression in hepatic stellate cells prepared from wild-type mice revealed high expression of PGE₂ receptor EP₂. We next stimulated hepatic stellate cells with TGF-beta and IL-1beta to activate them. Activated hepatic stellate cells showed increased expression of fibrosis-related factors mRNA such as type 1 collagen and CTGF, however, pretreatment with an EP₂ agonist significantly suppressed the increased expression of these mRNAs, and this inhibitory effect of EP₂ agonist disappeared in EP₂^–/– hepatic stellate cells.
These results indicate a possibility that a selective EP₂ agonist become a therapeutic drug that suppress the development of liver fibrosis mediated by activated hepatic stellate cells.