Carbachol Induces Hepatocyte Proliferation, but Only in the Presence of Hepatic Nonparenchymal Cells

Abstract

Vagal hyperactivity correlates with enhanced DNA synthesis and cell proliferation in the peripheral tissues of ventromedial hypothalamic (VMH)–lesioned rats. The infusion of an ACh receptor agonist, carbachol (Cch), induces rat duodenal and pancreatic cell proliferation to a degree comparable to the VMH lesions. Whereas the VMH lesions also induce the proliferation of hepatic cells, it is unclear whether Cch can also do this. Here we attempted to clarify the mechanism of hepatic cell proliferation induction by cholinergic stimulation. First, hepatic cell proliferation was examined in rats previously vagotomized and intraperitoneally administered with Cch via an osmotic minipump. Second, the sera from the Cch-infused rats were examined for a proliferative effect on isolated hepatic cells. And last, the effect of the presence of hepatic nonparenchymal cells (NPCs) on the proliferation of the cultured hepatocytes treated with Cch was investigated. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that the 3-day Cch infusion significantly increased the number of PCNA-immunoreactive cells in the liver. Moreover, the sera from the Cch-infused rats increased the number of PCNA-immunoreactive hepatocytes in culture. However, Cch alone did not induce proliferation in monocultured hepatocytes. When compared with the monoculture of hepatocytes, the coculture of those with hepatic NPCs resulted in enhanced PCNA immunoreactivity after a 4-day treatment with 3 mM Cch. These findings suggest that ACh induces hepatocyte proliferation, which is mediated by unidentified humoral factor(s) possibly secreted from hepatic NPCs, and that it also participates in liver hypertrophy in the VMH-lesioned animals.