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.Key words: acetylcholine, cell proliferation, liver, autonomic nervous system, obesity.The mechanism of obesity formation is quite complex.Because the causal relation with a serious disease such as diabetes is suggested in obesity, diversified analyses of the mechanism of the obesity formation are needed. As for the cause, besides overeating and physical inactivity, inheritance, medicine, and the hypothalamus are possible reasons.Neural obesity is also called hypothalamic obesity and includes the obesity induced by the lesions of the ventromedial hypothalamus (VMH) [1]. The VMH is involved in the autonomic regulation of feeding, sugar metabolism in the liver, and endocrine secretion of the pancreas [2]. Feeding decreases if VMH is electrically stimulated, whereas it increases if VMH is injured. Moreover, feeding increases if the lateral hypothalamus (LH) is activated and reduces if LH is suppressed. The VMH and LH are reciprocally regulated to each other; therefore it has been thought for a long time that the primary cause of neural obesity induced by VMH lesions is an overeating from hunger.It was reported in the 1960s, however, that obesity developed even if overeating was controlled by a pair-feeding experiment. Enhanced insulin secretion, which may result in hyperinsulinemia, arises in VMH-lesio...

Alpha7 Nicotinic Acetylcholine Receptor Mediates Nicotine-induced Apoptosis and Cell Cycle Arrest of Hepatocellular Carcinoma HepG2 Cells

“…It has been shown that nicotinic receptors activation can induce hepatocyte proliferation, but only in the presence of hepatic nonparenchymal cells. 36 Therefore, the role of other liver resident cells such as Kupffer cells and hepatic stellate cells in the diverse functions of α7nAChR in this organ should be carefully considered when investigating the toxic or proliferative effects of nicotine in the liver. In addition to apoptosis, it is clear that cell cycle arrest mediates apoptosis in a variety of diseases.…”

Vascular endothelial cells and smooth muscle cells mediate carbachol‐induced hepatocyte proliferation via muscarinic receptors and IP3/PKC signaling cascades

“…We checked the CIHP 72 h after Cch treatment because the number of proliferating hepatocytes peaked 3 days (72 h) after VMH lesioning (Kiba et al., 1998), as well as after the infusion of Cch (Yoshimura et al., 2007). Interestingly, the coculture with VECs even in the absence of Cch treatment significantly increased the number of hepatocytes compared to the monoculture in the absence of Cch (Fig.…”

“…We have shown that the infusion of carbachol (Cch; ACh agonist) and VMH lesions induce cell proliferation in pancreatic B‐cells and in epithelial cells of the duodenal crypts (Yoshimura et al., 2006). More recently, we found that the Cch‐induced expression of proliferating cell nuclear antigen (PCNA) in hepatocytes depends on the presence of hepatic nonparenchymal cells (HNPCs) (Yoshimura et al., 2007). The latter report strongly suggests that Cch‐induced hepatocyte proliferation (CIHP) is mediated by neighboring HNPCs, and also that cholinergic stimulus‐induced hepatic cell proliferation can occur even in the locally closed environment of the liver.…”