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Hepatology Research 2017; 47: 160–165
Review Article
Autonomic Nervous System and the Liver
Kei Mizuno1,2 and Yoshiyuki Ueno1,2
1
Department of Gastroenterology, Yamagata University Faculty of Medicine, and 2CREST, Yamagata, Japan
The liver is innervated by both the sympathetic and the parasym-
pathetic nerve systems. These nerves are derived from the
splanchnic and vagal nerves that surround the portal vein,
hepatic artery, and bile duct. The afferent fiber delivers informa-
tion regarding osmolality, glucose level, and lipid level in the por-
tal vein to the central nervous system (CNS). In contrast, the
efferent fiber is crucial in the regulation of metabolism, blood
INTRODUCTION
T HE RELATIONSHIP BETWEEN the autonomic ner-
vous system and GI tract has been previously de-
scribed. However, few reports have documented the
existence and role of the autonomic nervous in the liver.
In fact, the liver is affected by both the sympathetic and
the parasympathetic nerve systems. These nerve systems de-
liver information regarding hepatic osmolality, glucose
concentrations, and lipid concentrations to the brain
through the afferent neurons, and the liver receives varieties
of signals including blood flow, bile secretion, and metab-
olism through the efferent neurons.1,2 Orthotropic liver
transplantation (OLT) recipients lack these autonomic reg-
ulations since nerve fibers are cut and not reconstituted
during surgery. Nevertheless, this abnormality is typically
well tolerated by transplant recipients. Thus, the role of au-
tonomic nervous system in the liver received little attention
among hepatologists. However, increased obesity, dyslipid-
emia, hypertension, and diabetes mellitus (DM) have been
reported among OLT recipients following decades of liver
transplantation history.3,4 These observations suggest met-
abolic dysfunctions that may be caused by denervation of
the liver. In this short review article, the roles of the
intrahepatic autonomic nervous system are discussed.
Correspondence: Yoshiyuki Ueno, Department of Gastroenterology,
Yamagata University of Faculty Medicine. Email: y-ueno@med.id.
yamagata-u.ac.jp
Received 30 May 2016; revision 2 June 2016; accepted 3 June 2016.
© 2016 The Authors.
Hepatology Research published by John Wiley & Sons, Australia Ltd on behalf of The Japan Society of Hepatology
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs
License, which permits use and distribution in any medium, provided the original work is properly cited, the use is
non-commercial and no modifications or adaptations are made.
doi: 10.1111/hepr.12760
flow, and bile secretion. Furthermore, liver innervation has been
associated with hepatic fibrosis, regeneration, and circadian
rhythm. Knowledge of these mechanisms can be applied for
potential liver disease treatment.
Key words: autonomic nervous system, glucose metabolism,
hepatic fibrosis, lipid metabolism, liver innervation
Anatomy of autonomic nervous system in the
liver
In the liver, two autonomic nervous fibers are present: 1)
sympathetic neuron connected to the thoracic spinal cord,
and 2) parasympathetic neuron derived from the vagus
nerve. The sympathetic neuron follows the preganglionic
neuron derived from the intermediolateral column (lateral
horn) of the spinal cord (T7 to T12). It is considered as a
postganglionic neuron derived from either the celiac or
the superior mesenteric ganglion.1,5 In contrast, the para-
sympathetic neuron branches off from the vagal nerve
and regulates neurologically, either directly as a pregangli-
onic neuron originated from the dorsal motor nucleus in
the brainstem or indirectly by forming a synapse at the he-
patic hilar.1,5 These neuron fibers or neurons are distrib-
uted in the liver from the hilar of the hepatic portal and
subsequently branch off together with the hepatic arteries
and portal veins. Nerve distribution in the liver is diverse
among mammals, although most species share common
structures such as the sympathetic and parasympathetic
neurons surrounding the hepatic arteries, portal veins,
and intrahepatic bile ducts.5,6
Glucose metabolism
Glucose level is sensed by neurons and glial cells express-
ing glucose transporters (GLUT) in the central nervous sys-
tem (CNS) and in peripheral tissues such as the taste buds,
gut, and carotid body.7,8 In the liver, glucose level is also
160
Hepatology Research 2017; 47: 160–165
sensed at the portal veins.9 In the pancreas, GLUT2 regu-
lates glucose uptake and insulin secretion, whereas in the
liver, GLUT2 acts as a glucose sensor and monitors blood
glucose level in the portal vein.10,11 Decreased glucose
level in the portal vein activates the afferent vagal neuron,
which signals for an increase in food intake.12,13 However,
profound decrease in blood glucose level appears to be
sensed in the brain, and only a gradual decrease of the
portal blood glucose level prompts the increased food
intake.14–16 In contrast, high blood glucose level in the
liver itself does not suppress food intake.13
Incretins, such as the glucagon-like peptide-1 (GLP-1),
are hormones released from the small intestine to regulate
blood glucose level.17 GLP-1 is released into the portal
blood flow following appropriate food stimuli and ulti-
mately binds to its receptors expressed by the afferent neu-
rons in the portal area.18 The binding of GLP-1 to its
receptors activates the vagal nerve, which subsequently
modulates the pancreatic release of insulin via the efferent
sympathetic neuron signals (Fig. 1).19
Following efferent fiber activation, glucose production is
increased through stimulation of the splanchnic nerves (a
type of sympathetic nerve), while glycogen production is
suppressed.20 In contrast, glucose production is reduced
and glycogen production is increased by vagal nerve stimula-
tion (Fig. 2).21 Following denervation of the vagus nerve sys-
tem, hypoglycemic action of postprandial insulin secretion
is decreased, which may elevate blood glucose level.2,22 In
rat, hepatic insulin sensitivity is decreased following
Figure 1 The hepatic afferent nerves and glucose metabolism.The
afferent vagal nerves are activated by decreased portal glucose
level, increasing the intake of food. Glucagon-like peptide-1
(GLP-1) released into the portal blood flow stimulates the afferent
vagal nerves. This signal affects the pancreatic efferent sympathetic
nerves to release insulin. Red arrows: the effect of hypoglycemia in
the portal vein, green dotted arrows: the effect of GLP-1. [Colour
figure can be viewed at wileyonlinelibrary.com]
Hepatology Research published by John Wiley & Sons, Australia Ltd on behalf of The Japan Society of Hepatology
Autonomic nervous system and the liver 161
Figure 2 The hepatic efferent nerves and glucose metabolism.Ac-
tivation of the sympathetic efferent nerves increases glucose pro-
duction and suppresses glycogenesis. Stimulation of the vagus
nerves reduces glucose production and increases glycogenesis. He-
patic insulin sensitizing substance (HISS) is secreted by the liver
via parasympathetic efferent signals, promoting the skeletal mus-
cle to increase glucose storage. Purple arrows: the effect of the
sympathetic efferent nerves on glucose metabolism, green dash
arrows: the effect of the vagal nerves on glucose metabolism.
[Colour figure can be viewed at wileyonlinelibrary.com]
dexamethasone administration to the arcuate nucleus in
the hypothalamus. This action is believed to be mediated
by the sympathetic fiber of the liver, which expresses neuro-
peptide Y.23 Two mechanisms for the hypoglycemic effects
of insulin have been described: 1) through the effect of he-
patic insulin sensitizing substance (HISS) and 2) through
direct action of insulin.2 HISS is secreted by the liver and
acts on the skeletal muscle to accelerate glucose accumula-
tion.24 HISS is controlled by the parasympathetic nerve and
its effects are decreased by denervation of the parasympa-
thetic nerve system, resulting in insulin resistance.24
Net hepatic glucose uptake (NHGU) may be lost follow-
ing complete denervation of the hepatic nerve.25 Increased
level of both insulin and glucagon in the blood, and loss of
reactive increase of epinephrine/cortisol during hypoglyce-
mia have been reported in liver transplant recipients.26
Thus, the liver is thought to control the homeostasis toward
hypoglycemia and insulin response during hyperglycemia
through the action of the autonomic nervous system.
Lipid metabolism
Liver is a crucial organ for lipid metabolism. During lipid
metabolism, the synthesis and secretion of very low-
density lipoprotein (VLDL) and ketone body, and oxida-
tion of fatty acid are critical. In an experimental animal
model, blood glucose level is decreased and serum triglyc-
eride (TG) and cholesterol levels are increased following
denervation of the liver.27 Afferent fiber of the vagal nerve
© 2016 The Authors.
162 K. Mizuno, and Y. Ueno
detects intrahepatic free fatty acid concentration, which af-
fects feeding behavior.28 When lipids are administered
through the portal vein, afferent fiber of the hepatic vagal
nerve is stimulated, negatively regulating food intake
(Fig. 3).29,30 Furthermore, activation of the afferent fiber
promotes fat deposition and is important for the mainte-
nance of serum metabolite level.30 In diabetic patients,
triglyceride-rich VLDL (VLDL-TG) is secreted in excess,
which causes dyslipidemia. The hypothalamic area and au-
tonomic nervous system regulate VLDL-TG, and the he-
patic sympathetic nerve is crucial to maintain the VLDL-
TG secretion during fasting.31 Following denervation of
sympathetic neurons, the VLDL-TG secretion by neuropep-
tide Y neurons in the hypothalamus is impaired.31 Hepatic
TG level is associated with hepatic steatosis, and hepatic
TG is thought to be involved in the pathogenesis of meta-
bolic syndromes such as hyperphagia and obesity. Leptin,
secreted by adipocytes, is known to constrain feeding and
activate the hepatic sympathetic nerve via the CNS,
resulting in reduced liver TG level.32 Furthermore, dener-
vation of the hepatic sympathetic nerves causes decreased
carnitine palmitoyltransferase (CPT), which transfers long
chain fatty acids into the mitochondria.33 Sympathetic
stimulation regulates the secretion of lipoproteins includ-
ing TG and apo-B as well as the release of VLDL. Following
denervation of the hepatic sympathetic nerves, VLDL secre-
tion is increased and plasma level of cholesterol and TG is
elevated accordingly.27 Hepatic sympathetic innervation
also affects ketone body metabolism. Sympathetic stimu-
lation promotes ketone body production and its release
from the liver.34
Figure 3 The hepatic nerves and lipid metabolism. Increased lipid
level in the portal vein stimulates afferent fiber of the hepatic vagal
nerves, suppressing the intake of food. Leptin secreted by
adipocytes activates hepatic sympathetic nerves via the central ner-
vous system (CNS), decreasing the triglyceride (TG) content in the
liver. Green dash arrows: the effect of increased lipid level in the
portal vein, blue dotted arrows: the effect of leptin toward lipid me-
tabolism. [Colour figure can be viewed at wileyonlinelibrary.com]
© 2016 The Authors.
Hepatology Research published by John Wiley & Sons, Australia Ltd on behalf of The Japan Society of Hepatology
Hepatology Research 2017; 47: 160–165
Maintenance of fluids
Osmotic pressure of extracellular fluid is strictly regulated
by the osmosensing system that involves multiple organs.
This system balances the uptake and excretion of salt and
water, which are controlled by signals from the brain.
The liver detects early changes in plasma osmolality, and
the body subsequently makes appropriate adjustments to
these changes.35
The hepatic nerve utilizes specific ion channels, which
are specifically activated by osmolality changes for osmo-
lality sensing.1 Among these receptors, the transient recep-
tor channel protein vanilloid 4 (TRPV4), was recently
reported to respond to osmotic changes and to play a role
in controlling ion currents.35 When the brain senses hypo-
tonic stimulation via TRPV4, the signal is communicated
through the afferent fiber derived from the dorsal root gan-
glia in the thoracic part of the spinal cord (Fig. 4). Osmo-
lality is decreased after water consumption and pressor
reflex appears to be induced by the efferent sympathetic fi-
ber, which is activated by afferent stimulus.36,37
The hepatic nerve system is also capable of detecting
changes in ion concentrations, similar to osmo-sensing
prior to systemic circulation.38 As the concentration of
substance absorbed into the portal vein reaches level that
is four to five-folds higher than that of the systemic circula-
tion, the hepatic nerve can detect changes in ion concentra-
tion earlier than any other organs.39 Greater increase in
urinary excretion is observed when equal amount of water
enters the portal vein compared to when water enters any
Figure 4 The hepatic afferent nerves and fluid maintenance.
When decreased portal osmolality is detected, afferent stimulation
via dorsal root ganglion activates the efferent sympathetic fiber to
induce pressor reflex. Hypernatremia in the portal vein detected
by the hepatic afferent nerves decreases renal sympathetic tone.
This causes the downregulation of sodium resorption and in-
creased urinary excretion. Red arrows: the effect of decreased por-
tal osmolality, blue arrows: the effect of hypernatremia. [Colour
figure can be viewed at wileyonlinelibrary.com]
Hepatology Research 2017; 47: 160–165
other systemic veins. This phenomenon is known as the
hepatorenal reflex. This reflex causes activation of the affer-
ent hepatic fibers and suppression of the efferent renal
sympathetic nerve following hypertonic water load in the
portal vein ultimately resulting in the downregulation of
sodium reabsorption in the renal tubules.40 Hepatorenal
reflex is thought to be involved in the pathogenesis of
hepatorenal syndrome, which is frequently observed in
end-stage cirrhotic patients.39
Regulation of blood flow and bile
The autonomic nervous system is crucial in maintaining
blood flow in the liver. Following hepatic autonomic
nerve stimulation, reduction in hepatic arterial blood flow
is observed.41 This is mediated by an alpha adrenergic
receptor-dependent mechanism through constriction of
the hepatic artery. Thus, following sympathetic nervous
system activation, contraction of the hepatic artery and de-
creased sinusoidal wall permeability are initiated, which is
then followed by decreased total hepatic blood flow.42 He-
patic sinusoidal lining cells filter blood from the portal on
systemic circulation. The sinusoid displays a capillary mor-
phology lined by sinusoidal endothelial cells (SEC) and
surrounded by hepatic stellate cells (HSC). The terminus
of hepatic efferent nerve fiber is thought to be distributed
around the stellate cells located on the sinusoidal wall.
Further, the hepatic efferent nerve is thought to regulate
constriction of the sinusoids.1,43 While sympathetic release
of adrenalin and substance P induces contraction of the
hepatic sinusoids, parasympathetic release of acetylcholine
and vasoactive intestinal peptide (VIP) causes sinusoidal
relaxation.44 Sympathetic stimulation is believed to aid
contraction of hepatic artery. The sinusoid plays an impor-
tant role in reducing hepatic blood flow following bleed-
ing and ultimately contributes to the maintenance of
circulating blood volume.42
Bile duct epithelium (cholangiocyte) is also controlled
by the autonomic nervous system. Cholangiocytes regulate
bile flow (choleresis) by controlling the secretion and ab-
sorption of bile acid and bicarbonate during their passage
between the bile canaliculi.45 Following food intake, the
predominant parasympathetic system increases bicarbon-
ate secretion and subsequent bile secretion. Vagotomy
was shown to disrupt the secretin-dependent choleresis.46
Moreover, acetylcholine appears to induce proliferation
of the cholangiocytes.46,47 Cholangiocytes express both α
and β adrenergic receptors and receive signals from the
sympathetic nervous system.48,49 Following stimulation
of the α1 adrenergic receptor, both secretin-induced
choleresis and Ca2+/cAMP-dependent proliferation of
cholangiocytes are induced. In contrast, stimulation of
Hepatology Research published by John Wiley & Sons, Australia Ltd on behalf of The Japan Society of Hepatology
Autonomic nervous system and the liver 163
the α2 adrenergic receptor results in decreased choleresis
mediated by secretin.49,50 However, the dopaminergic sys-
tem was shown to exert conflicting actions related to the
secretin-induced choleresis in an experimental hepatic
cholestasis model.51
Hepatic fibrosis and regeneration
HSCs in the hepatic space of Disse are activated following
hepatic injury and transformed into myofibroblasts that
produce collagen fibers.52 HSCs express the adrenergic re-
ceptor and are thought to be regulated by the autonomous
nervous system.53 Impaired norepinephrine action causes
repression of HSC growth and decreased collagenous fiber
production. During severe acute liver damage or chronic
liver injury, hepatic stem cells differentiate into hepato-
cytes or cholangiocytes.54 Hepatic oval cells (HOCs) are
thought to be the candidate hepatic stem cells or progeni-
tor cells. In the normal liver, HSCs and HOCs are quies-
cent; however, they are activated after specific hepatic
injury. In rats, liver regeneration after partial hepatectomy
was impaired following vagotomy, implicating important
role of the parasympathetic nervous system.55 Further-
more, inhibition of the sympathetic nervous system was
shown to result in increased number of HOCs.53 To sum-
marize, HOC proliferation is inhibited after hepatic sym-
pathetic stimuli, and HSCs are activated to promote
hepatic fibrosis. These events are consistent with the cir-
rhotic state; thus, sympathetic nervous system inhibitors
may be applied for potential hepatic cirrhosis treatment.
Circadian rhythm
The circadian rhythm is a physiological phenomenon in
which various fundamental biological activities including
sleep and diet vary within a cycle that is approximately
24 hours in length. The circadian rhythm is regulated by
genes referred to as the clock genes, which are expressed
in the suprachiasmatic nucleus designated as the internal
master clock.56 However, related clock genes are also
known to be expressed elsewhere in the body.56 Denerva-
tion of the sympathetic nervous system in the liver abol-
ishes the normal circadian changes in blood glucose
level, although the expression of clock genes is not af-
fected.57 However, following complete denervation of
the liver, no abnormalities of blood glucose level rhythm
were observed, implicating the importance of autonomic
nervous system balance to control daily variations of
blood glucose concentration.58 Several genes expressed in
the liver follow a circadian rhythm, and most of these
genes were shown to be responsible for metabolic con-
trol.59 Thus, the circadian rhythm appears to be involved
in the hepatic metabolism and detoxification of drugs.
© 2016 The Authors.
164 K. Mizuno, and Y. Ueno
SUMMARY
T HE HEPATIC AUTONOMIC nervous system transmits
information from the liver to CNS. It also regulates he-
patic functions, as instructed by signals from the CNS. Ef-
fects of these signals are not limited to the liver, but also
influence the brain and other autonomic nervous systems
to maintain systemic homeostasis. However, numerous
mechanistic details related to the autonomic nervous sys-
tem and liver are yet to be addressed. Further studies, espe-
cially those related to human diseases such as chronic liver
diseases and liver cirrhosis, are feasible. These studies may
yield potential therapeutic applications.
ACKNOWLEDGMENTS
P UBLICATION OF THIS manuscript is supported in
part by CREST (Innovation for Ideal Medical Treat-
ment Based on the Understanding of Maintenance,
Change and Breakdown Mechanisms of Homeostasis
among Interacting Organ Systems) from AMED and
Grant-in-Aid for Young Scientists (B) from JSPS KAKENHI
Grant Number 26870066 (to KM).
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