Muscarinic receptor mediated signaling pathways in hepatocytes from CCL4 - induced liver fibrotic rat

The pathological changes of parasympathetic nerves are considered as an independent prognostic factor of the survival rate for patients with chronic liver disease. The non-selective muscarinic acetylcholine receptors (mAchR) agonists and antagonists can affect the proliferation of hepatocytes, but little is known about the role of mAChR in hepatocytes and hepatic fibrosis and the signaling pathway of this receptor in regulation of hepatocytes remains elusive. Here, 3 ml/kg 40% carbon tetrachloride (CCL4) was given to induce hepatic fibrosis in rats and the hepatocytes were isolated to investigate the expression of mAchR and the cell signaling pathways which were involved in. Compared with the normal state, the expression levels of m1, 3, 5 in fibrotic hepatocytes (FHC) and the cells treated with 10 μM pilocarpine (Pi) were obviously increased, while decreased in m2,4. Pi could increase the value of alanine aminotransferase (ALT), hydroxyproline (Hyp), decrease albumin (ALB) and cell viability, while atropine could ameliorate fibrotic hepatocytes fuction. The p-AKT, p-ERK, p- JNK and p-P38 increased in Pi group or FHC group, but the inhibitors of PI3K, MAPK and PKC could reverse the Pi action and improve the FHC fuction. In this study we found that mAchR played an important role in the regulation of hepatic fibrosis process and the PKC, ERK, P38 and PI3K/AKT signaling pathways involved in the parasympathetic excitation mediated by mAchR.