The SNS contributes to the development of non-alcoholic fatty liver disease and hepatocellular carcinoma (Table 1). In liver injury models, increased expression of alpha and beta-adrenergic receptors (α/β-AR) and neuropeptide Y (NPY) receptors on HSCs promotes liver fibrosis and cirrhosis by inducing HSCs proliferation and secretion of inflammatory factors. Epinephrine (EPI) and norepinephrine (NE) induce the production of collagen-1α2 (COL1A2), transforming growth factor-beta (TGF-β), and induce the activation of NF-κB by acting on HSCs [1,3]. Moreover, the SNS promotes liver inflammatory microenvironment formation and hepatocellular carcinoma development by regulation of interleukin (IL)-6 and TGF-β through activation of α1-AR on KCs [4]. Soeda et al. [5] showed that the SNS inhibits HPC and promotes liver injury by activating α1-AR. However, β-AR agonist isoproterenol-mediated β-AR activation rescues acetaminophen (APAP)-induced liver injury by promoting HPC proliferation through Wnt signaling activation.

In contrast to the SNS, vagal signaling exerts protective effects on hepatic damage (Table 1). In a mouse model, the cholinesterase inhibitor neostigmine reduced APAP-induced acute liver failure and improved the survival rate of the mice [6]. The α7 nicotinic acetylcholine receptor (α7AChR) agonist exhibits an anti-apoptotic effect on Fas-induced hepatitis by suppressing KC-generated reactive oxygen species [2]. Moreover, parasympathetic nerve-secreted acetylcholine (Ach) inhibits expression of tumor necrosis factor (TNF) and IL-6 through activation of Src kinase by acting on the α7AChR of KCs, thus suppressing lipopolysaccharide-induced hepatitis [7].

Muscarinic acetylcholine receptor type 3 (M3 AChR) is proven to be expressed on the surfaces of cholangiocytes and HPC. Activation of M3 AChR plays an important role in cholangiocyte and HPC proliferation, anti-apoptosis, and liver regeneration [1]. Furthermore, PNS activation increases the expression of IL-6 in macrophages by acting on muscarinic Ach receptors (mAChRs). Furthermore, IL-6 promotes hepatic FoxM1 activation that stimulates hepatocyte proliferation through signal transducers and activators of transcription 3 [8]. Therefore, parasympathetic signaling may be a potential therapeutic target for patients with liver injury, hepatitis, and hepatic tumors.

However, studies showed that NE promoted hepatocellular carcinoma metastasis through α1/β2-AR activation, while the vagus nerve had a suppressive role in liver metastasis in mice [2,9]. Moreover, In a mouse model of Fas-induced fulminant hepatitis, the release of NE by the SNS demonstrates an anti-apoptotic and hepatoprotective effect by up-regulating the expression of IL-6 [10]. Notably, these studies were carried out in animal models, and many of these studies employed systemic administration of chemical sympathectomy, which does not selectively affect the liver. Therefore, further investigation is needed to clarify the role of the autonomic nervous system in liver.