During our training in the 1970s or earlier, many of us were told that hepatic nerves were of lesser importance because “the liver was sparsely innervated as compared to other organs” and because “a transplanted liver does well in spite of its absolute denervation.” In view of the wealth of new studies that have come out in the past 20 years, the above view can no longer be maintained. The purpose of this special issue of the Anatomical Record is to summarize our current knowledge on hepatic innervation. While the plan to compile this issue was maturing, the news broke that Dr. Kurt Jungermann had passed away. We are all very much indebted to this pioneer in liver research who made major contributions to our current insights into liver innervation and into neural signal propagation. The current issue of the journal can be subdivided into three parts. The first five articles describe in detail the anatomy and microanatomy of the nervous system in embryonic and adult liver and in the gallbladder. The next seven studies deal with the varied functions of the hepatic nervous system. The last article describes the physiological changes brought about by surgical liver denervation and discusses the implications of these changes following liver transplantation. In contrast to the esophagus, stomach, intestines, pancreas and gallbladder, the liver does not contain an “intrinsic nervous system,” i.e., it does not contain perykarya of neurons organized in ganglia. Delalande et al. address the question as to why the early embryonic liver is not colonized by neural crest cells, as is the case with the intestine, the pancreas, and the gallbladder. Lack of expression of glial cell line-derived neurotrophic factor (GDNF) and of netrin may be at the basis of this lack of colonization. From a functional point of view, the embryonic liver may not need innervation, as its primary function at the embryonic stage is hematopoietic rather than metabolic. Only postnatally, the role of the liver changes into a vital metabolic organ requiring modulation via the nervous system. By then, the possibility of colonization by neural crest cells and their subsequent differentiation into intrahepatic neurons and glial cells has long gone. Uyama et al. describe the two ways in which the hypothalamus communicates with the liver: via autonomous nerves and via neuroendocrine connections. The article summarizes the anatomy of the neural connections and neuroendocrine pathways that connect the liver to the hypothalamus. It also mentions what we do not know yet: the exact neural pathways by which efferent parasympathetic nerves affect the liver; the functions of hepatic afferent nerves; the distribution of neuropeptidergic nerves in diseased liver; the functions of hepatic neurotransmitter- or neuropeptide-containing nerves in normal and diseased liver; and the involvement of neuroendocrine pathways in regulation of normal and diseased liver functions. McCuskey discusses in detail the anatomy of efferent (motor) hepatic nerves and the various neurotransmitters released by their motor end plates. There is considerable variation between species when it comes to intralobular innervation. This variability may explain some of the diverse hemodynamic and metabolic responses reported as a result of hepatic nerve stimulation. Berthoud reports on the anatomy and function of afferent (sensory) hepatic nerves. The latter has not been studied as thoroughly as the innervation of other organs. Afferent nerves from vagal or dorsal root/spinal origin are restricted to the stroma surrounding the hepatic vasculature and bile ducts and to the extrahepatic portions of the portal vein and bile ducts. Only a minor portion of the common hepatic branch of the nervus vagus innervates the liver. The major portion descends toward duodenum, pancreas, and pylorus. Finally, the specific anatomical organization of hepatic nerves makes it nearly impossible to perform selective hepatic denervation, whether selective for the vagal or sympathetic division or for efferents or afferents. Balemba et al. describe the innervation of the extrahepatic biliary tract. In contrast to the liver, the bile ducts and gallbladder contain extrinsic and intrinsic nerves. In the embryo, the intrinsic nerve cells derive from migrating neural crest cells, as is the case in the gut. However, the structural, neurochemical, and physiological characteristics of gallbladder neurons are different from those of the enteric nervous system. The second part of this issue deals with the multiple functions of hepatic nerves. The functions include regulation of a host of metabolic processes that take place in hepatocytes; regulation of hepatic osmolytes and modulation of hepatocellular hydration; innervation of hepatic sinusoidal cells and in particular of stellate cells, thereby regulating sinusoidal blood flow; innervation of the hepatic neural/neuroendocrine compartment consisting of hepatic progenitor cells and stellate cells and concomitant modulation of the phenotype of these cell types; innervation of dendritic cells, as well as T-, NKT, and NK lymphocytes that are strategically positioned in the portal triads, and modulation of their immune functions; and neural control of the circadian rhythm of the liver. Püschel has summarized our current knowledge on the neural control of metabolic liver functions. These functions include glucose homeostasis and other aspects of hepatic carbohydrate metabolism, cholesterol synthesis, fatty acid oxidation and VLDL formation, bile secretion, amino acid metabolism, urate formation, xenobiotic metabolism, and osmolyte exchange. Given the rapid increase in the incidence of a new disease entity, namely, nonalcoholic fatty liver disease (NAFLD), which is closely associated with hepatic insulin resistance, the question arises as to what extent the hepatic nervous system takes part in the pathogenesis of NAFLD. Häussinger addresses regulation of hepatic osmolyte exchange and concomitant volume adaptation of hepatocytes and nonparenchymal liver cells. Hepatic osmolytes are important modulators of liver cell function with impact in healthy and diseased liver. Efferent sympathetic nerves have a direct effect on hepatocellular hydration and osmolyte balance. α-adrenergic stimulation leads to hepatocyte swelling. Whether stellate cells undergo similar swelling is unknown. Cell swelling may contribute to increased intrahepatic vascular resistance and portal hypertension. Hepatic afferent nerves regulate hepatocellular hydration via indirect mechanisms that affect ADH secretion. Ueno et al. describe that stellate cells, sinusoidal endothelial cells, and possibly Kupffer cells are innervated by efferent nerve endings, which modulate the various functions of these cells. Stellate cells respond to noradrenaline by contraction. Since stellate cells are strategically located around sinusoidal endothelial cells, contraction of stellate cells may lead to a decrease of the sinusoidal diameter and hence to increased sinusoidal resistance and pressure, thereby contributing to portal hypertension. Oben and Diehl describe the modulation of stellate cells and oval cell phenotype by sympathetic innervation. Increased sympathetic activity leads to increased release of noradrenaline and neuropeptide Y (NPY). These neurotransmitters activate stellate cells and suppress oval cell proliferation. Conversely, inhibition of sympathetic activity leads to suppression of stellate cell activation and enhanced proliferation of oval cells. Moreover, stellate cells act as hepatic neuroglia cells by perisinusoidal secretion of noradrenaline. These observations have major implications for future research on hepatic fibrosis and bring the question of the embryonic origin of stellate cells to the forefront. Along the same lines, Roskams et al. propose a new concept, namely, the neural/neuroendocrine compartment of the liver. This compartment comprises hepatic progenitor (oval) cells and hepatic stellate cells. Both cell types carry a host of neural markers and contain vesicles with synaptic or endocrine characteristics. The authors present evidence that this compartment is under the direct control of parasympathetic innervation. Their work has major implications for the field of hepatology. Indeed, hepatic progenitor cells and stellate cells are effector cells in regeneration and repair and might also be required to create the right environment for reinnervation of diseased or renewed tissue. Neuhuber and Tiegs describe that efferent adrenergic sympathetic neurons alleviate, while capsaicin-sensitive peptidergic primary afferent neurons aggravate, immune-mediated liver injury. Dendritic cells, as well as T-, NKT, and NK lymphocytes, are strategically positioned in the portal triads, thereby allowing direct contacts with afferent and efferent nerve endings. Kupffer cells and sinusoidal NKT cells are at a larger distance from nerve terminals, especially in rodents, but could be influenced via diffusion of aminergic or peptidergic neurotransmitters. These observations form the anatomical basis that explains how the nervous system modulates immune functions. Shibata has covered the fascinating topic of neural regulation of hepatic circadian rhythm. Clock genes play a critical role in the regulation of circadian rhythm, both in the central nervous system and in peripheral organs such as the liver. As many as 10% of genes are under the control of clock genes. The efferent adrenergic nerves modulate hepatic circadian rhythm. Intrahepatic noradrenaline concentration oscillates with time. Chemical sympathetic denervation abolishes this oscillating pattern. Taking into account that stellate cells are intrahepatic cellular sources of noradrenaline (Oben and Diehl in this issue), the question arises as to what extent stellate cells are pacemakers of hepatic circadian rhythm. In the third part of this issue, Colle et al. address the clinically important question of the consequences of the absolute denervation of a transplanted liver allograft. In patients, hepatic denervation following liver transplantation has no major effects on bile secretion, liver regeneration, and hepatic blood flow. However, it induces insulin resistance, postprandial hyperglycemia, changes in ingestion behavior, and reduced stimulation of hepatic progenitor cells. The idea of promoting extrinsic hepatic reinnervation following transplantation is appealing. Partial reinnervation has been reported to occur in experimental animals after surgical denervation or experimental transplantation. Future research endeavors will have to make out whether, and under which conditions, the neural/neuroendocrine compartment favors reinnervation. There is still work to be done to advance our basic knowledge of hepatic innervation. However, with all the progress that has been made in understanding the anatomy, microanatomy, cell biology, and physiology of hepatic nervous system, new opportunities have arisen to develop novel therapeutic modalities that target the hepatic nervous system for treatment of chronic liver diseases and their often dreadful complications.

Albert Geerts

The Anatomical Record

The Anatomical Record is an academic journal focused on the field of anatomy, covering both fundamental and applied research, aimed at promoting scientific communication and advancement in anatomy.

《解剖记录》是一本专注于解剖学领域的学术期刊，涵盖了相关的基础研究和应用研究，旨在促进解剖学的科学交流与发展。

Hepatic nervous system: Foreword

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