The hepatic vagus nerve stimulates hepatic stellate cell proliferation in rat acute hepatitis via muscarinic receptor type 2

Abstract

Background & Aims:We have previously shown that the hepatic vagus nerve stimulates the activation of hepatic progenitor cells (HPC), via muscarinic acetylcholine receptor type 3. Given the coproliferation of HPC and hepatic stellate cells (HSC) in acute hepatitis, we determined whether HSC proliferation is also modulated by vagal activity. Methods: We induced acute hepatitis in Wistar rats by injection of galactosamine and lipopolysaccharides. Hepatitis was preceded by hepatic branch vagotomy or sham vagotomy, by electrical stimulation or sham stimulation and by muscarinic receptor antagonist atropine, nicotinic receptor antagonist mecamylamine or saline injection. Rats were sacrificed after 12 and 48 h and HSC numbers were quantified on immunohistochemical stainings. Furthermore, we performed reverse transcriptase-polymerase chain reaction with receptor-specific primers on total RNA from isolated HSC and determined the in vitro proliferation of HSC in response to acetylcholine, atropine and mecamylamine. Results: HSC numbers were significantly lower after vagotomy than after sham vagotomy. Conversely, more HSC were seen after electrical stimulation than after sham stimulation. Atropine resulted in less HSC than saline at both time points, while mecamylamine treatment only diminished HSC after 12 h, suggesting a predominant involvement of muscarinic receptors. Moreover, HSC express muscarinic receptor type 2 mRNA and protein, as well as nicotinic receptor a1, a5, b1 and vasoactive intestinal peptide receptor 1 mRNA. Furthermore, acetylcholine enhanced the in vitro proliferation of HSC, which was inhibited by atropine, but not by mecamylamine. Conclusions: We show here that the hepatic vagus nerve stimulates HSC proliferation, most likely through binding of acetylcholine on muscarinic receptor type 2.

M1 Muscarinic Receptor Deficiency Attenuates Azoxymethane-Induced Chronic Liver Injury in Mice

“…Previous studies showed that nicotinic acetylcholine receptor (nAChR) stimulation augments stellate cell activation 53 54 ; while another study suggested nAChR play a lesser role. Although we observed very low M1R expression in stellate cells isolated from mouse livers 14 , M2R may be involved in stellate cell proliferation 55 . Divergent findings may also result from different experimental models.…”

Decreased risk of liver and intrahepatic cancer in non-H. pylori-infected perforated peptic ulcer patients with truncal vagotomy: a nationwide study

“…However, the hepatic nervous system has been reported to modulate 38 as well as activate HSCs during liver carcinogenesis 47 . The hepatic vagus nerve was reported to stimulate HSC proliferation via muscarinic receptor type 2 48 and stimulate activation of the HPC compartment via muscarinic acetylcholine receptor type 3 49 . In addition, hepatic branch vagotomy may suppress liver regeneration in partially hepatectomized rats 50 , 51 .…”

“…It is likely that there was persistent vagal hyperactivity in PPU patients who underwent simple suture (i.e., integrated vagal nerve). Persistent vagal hyperactivity may stimulate HSC proliferation and activate HPC 48 , 49 , which promotes fibrosis and dysregulates liver regeneration, as well as lead to the progression of HCC and ICC 44 . It is plausible that vagotomy alleviates persistent vagal hyperactivity in PPU patients and results in a decreased incidence of HCC and ICC.…”

A comparative study of subsequent liver cirrhosis risk in non‐Helicobacter pylori‐infected peptic ulcer patients with and without vagotomy: An Asian population cohort study

“…7 The hepatic parasympathetic nerves branch off the vagus nerve and are thought to innervate the liver. 1,2 There was a report that hepatic vagus nerve stimulated HSC proliferation in a rat model via muscarinic receptor type 2, 30 and vagal nerve stimulated activation of the HPC compartment via muscarinic acetylcholine receptor type 3. 31 Studies showed that subdiaphragmatic vagotomy severely impaired liver regeneration after partial hepatectomy in a rodent model.…”

“…37,38 In the current series, complicated peptic ulcer patients who underwent vagal nerve severance were associated with a lower HR of subsequent cirrhosis than were those without vagal nerve severance. It is likely that there was persistent vagal hyperactivity in peptic ulcer patients without vagotomy, and persistent vagal hyperactivity may keep stimulating HSC proliferation and activating HPC, 30,31 leading to progressive fibrosis and dysregulated liver regeneration in peptic ulcer patients, resulting in progressive cirrhosis. 28 Patients undergoing vagal nerve severance had a 1.36-fold increased risk of cirrhosis compared with the general population ( Table 2).…”