University of Central Florida Undergraduate Research Journal - Anatomy and Function of Autonomic Innervation of the Liver
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Anatomy and Function of Autonomic Innervation
of the Liver

By: Kennan Negrete | Mentor: Dr. Zixi Cheng


This paper has offered an overview of the current literature surrounding the anatomy and physiology of autonomic innervation of the liver and has explored the interaction between the CNS and hepatic tissue to maintain homeostasis and regulate metabolism. However, this review would be incomplete without an analysis of the issues that remain unresolved, as well as the directions future studies may take to answer these questions. First, it is worth noting that much of the information contained in this review was drawn from studies that are many years, even decades old. There thus exists a lack of recent literature regarding hepatic innervation. The paucity of information concerning the liver-brain axis would suggest one of two possibilities: either that limited progress has been made, or that the discouraging lack of knowledge regarding the topic has sidelined it in favor of other targets. In either case, the fact that relatively little recent literature exists means that much of the current knowledge surrounding liver innervation is in dire need of an update. Study of these topics was likely limited by the technology of the past, but with modern advances in microscopy, tissue sectioning, and labelling, new studies could be undertaken to not only validate the predecessors but also discover new information. Among the most important issues to be addressed are the elusive intrahepatic ganglia. The idea that an organ as large, complex, and critical as the liver would lack such vital neural structures seems absurd, yet no such formation has been found to date (Berthoud, 2004; Berthoud and Neuhuber, 2000; Taher et al., 2017). An inability to find a structure is hardly compelling evidence that it is not present at all, especially given the dated methods used before. Thus, the search for intrahepatic ganglia must be continued.

The physiology of liver innervation has more gaps in the literature than the anatomy of the neurons themselves. More specifically, the current knowledge understands “what” sympathetic and vagal stimulation of hepatic tissue is likely responsible for, but “how” the mechanisms operate is largely unknown. For example, there is a suspected parasympathetic pathway of NPY function, but so far only the sympathetic arm has been elucidated in appreciable detail (Kalsbeek et al., 2010; Smith, 2018). TRH is known to induce hyperglycemia, but the mechanism behind this blood sugar spike is not available (Kalsbeek et al., 2010). This mechanism could be neural or endocrine, and involve autonomic pathways from the CNS, but only further study will be able to say for certain. Perhaps the strangest and most puzzling problem of all is how the liver functions without CNS innervation. Liver transplant patients have hepatic tissues that operate almost normally (Tiniakos, Lee, & Burt, 1996; Yi et al., 2010). If the liver-brain axis is as vital as some data suggest, why are denervated livers able to perform most of the same actions a normal liver can? The ambiguity surrounding the anatomy, function, and necessity of hepatic autonomic innervation makes this area a vital field of future study.

If any scientific progress is to be made toward a more complete understanding of liver innervation, more powerful, accurate, and thorough screening and denervation technologies must be brought to bear. Tracers such as calretinin and P2X2/X3 vesicular glutamate transporter have potential (Berthoud, 2004), but have been used to label liver tissue in few, if any, laboratory trials. Of even greater importance is the need for a reliable way to obliterate certain populations of hepatic neurons without harming unrelated nerves. This method would allow the functions of specific groups of neurons to be isolated according to type, origin, and secretions. Chemical and biological agents that specifically target sympathetic hepatic neurons may be especially important for treating liver cirrhosis and cancer, since sympathetic stimulation is partly responsible for the progression of these diseases (Baik et al., 2017; Huan et al., 2017; Jensen et al., 2013). Such technologies are within our capacity to develop and doing so will reveal the location of intrahepatic ganglia as well as elucidate the various CNS pathways that are currently incomplete.


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