Hepatic interoception in health and disease

Abstract

The liver is a large organ with crucial functions in metabolism and immune defense, as well as blood homeostasis and detoxification, and it is clearly in bidirectional communication with the brain and rest of the body via both neural and humoral pathways. A host of neural sensory mechanisms have been proposed, but in contrast to the gut-brain axis, details for both the exact site and molecular signaling steps of their peripheral transduction mechanisms are generally lacking. Similarly, knowledge about function-specific sensory and motor components of both vagal and spinal access pathways to the hepatic parenchyma is missing. Lack of progress largely owes to controversies regarding selectivity of vagal access pathways and extent of hepatocyte innervation. In contrast, there is considerable evidence for glucose sensors in the wall of the hepatic portal vein and their importance for glucose handling by the liver and the brain and the systemic response to hypoglycemia. As liver diseases are on the rise globally, and there are intriguing associations between liver diseases and mental illnesses, it will be important to further dissect and identify both neural and humoral pathways that mediate hepatocyte-specific signals to relevant brain areas. The question of whether and how sensations from the liver contribute to interoceptive self-awareness has not yet been explored.

Keywords: Brain; DRG neurons; Energy balance; Energy intake; Glucose sensing; Liver; Liver disease; Mental illness; Osmosensing; Spinal cord; Vagus nerve.

Fig. 1.. Schematic diagram showing signaling pathways between the liver and the brain.

Communication in both directions is accomplished by three major pathways, vagal, spinal, and humoral. Communication from liver, heptoportal vein, and bile ducts, to the brain is accomplished by vagal afferent neurons (VANs, 1), dorsal root ganglia neurons and the spinal cord (2), and by hepatokines and bilokines released into the blood stream (3). Signals generated in DRGs as well as humoral signals can also communicate with the enteric nervous system, postganglionic neurons, and the spinal cord via short loops. In addition to DRGs, the gut can also communicate to the spinal cord and postganglionic sympathetic neurons via intestinofugal neurons in the enteric nervous system (4). Communication from the brain to the periphery is accomplished by vagal efferents (5), the sympathetic nervous system (6) and neuroendocrine outflow (7). Note that specific signals generated in the liver can be mediated by multiple and mixed pathways to the brain and other peripheral organs. Abbreviations: BBB, blood-brain barrier; CVOs, circumventricular organs with missing blood brain barrier. Abbreviations: BBB, blood brain barrier, CVOs, cicumventricular organs; DMX, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius, VANs, vagal afferent neurons.

Fig. 2.. Fundamentals of liver architecture.

a: Three transversely sectioned classical liver lobules (yellow hexagons) each with a central vein are surrounding a portal canal containing branches of the hepatic portal vein, hepatic artery, and bile ducts. An “acinus” is defined as a functional unit consisting of a portal canal and parts of three adjacent liver lobules. b: Schematic diagram of lobular architecture with rows of hepatocytes (liver plates), liver sinusoids, and bile ducts in between. Note that gaps between endothelial cells allow free exchange of molecules between blood, hepatocytes, and nerve endings in the space of Disse (double arrow).

Fig. 3.. Vagal afferent and efferent innervation of the liver, hepatic portal vein, and bile ducts in rat and mouse.

a: Schematic diagram showing the distribution pattern of the common hepatic branch of the vagus in the rat. b: Montage of fluorescent microscope images of a whole mounted tissue block comprising the common hepatic branch and its bifurcations along the hepatic and gastroduodenal arteries from a rat 20 days after injection of the red-fluorescent dye DiI into the left nodose ganglion. Note the intensely fluorescent (bright white) two subbranches traveling along the hepatoesophageal artery (ahe) are associated with innervated paraganglia that contain glomus cells and a few neurons (insets). The hepatic branch proper mingles with the periarterial plexus surrounding the hepatic artery proper, while the larger gastroduodenal branch bypasses the liver area to descend along the gastroduodenal artery. c-e: Confocal images of DiI-labeled (bright white) axons and terminals in the connective tissue surrounding the hepatic artery (ahp, c), in the wall of a larger bile duct (d), and within the wall of the hepatic portal vein (e) (With permission from (Berthoud, 2004; Berthoud et al., 1992). f,g: Fluorescent microscope images of vagal afferent axons and terminals around the hepatic portal vein (hpv, f) and between a portal canal and hepatocytes in an adjacent liver lobule (g) from a mouse with cre-dependent AAV-TdTomato injected into the nodose ganglia of a Vglut-Cre mouse (from Bai & Knight et al, (Bai et al., 2019) with permission). h: Rare VAChT-immunoreactive nerve fiber (red) in the hepatic portal space of a rat with counterstained macrophages (green). Abbreviations: ac, celiac artery; agdd, gastroduodenal artery; ags, left gastric artery; ahe, hepatoesophageal artery; ahc, common hepatic artery; ahp, hepatic artery proper. Scale bars: b, 200 μm; c, e-g, 100 μm; d,h,i 20 μm.

Fig. 4.. Vagal efferent and sympathetic innervation of the liver.

a: Potential vagal postganglionic neurons located in small ganglion embedded in hepatic artery plexus. The ganglion is associated with a nerve bundle (n), containing neurons (arrowheads) and glomus cells (arrows), and is innervated by anterogradely DiI-labeled vagal efferent fibers (bright white). With permission from (Berthoud and Neuhuber, 2000). b: Rare VAChT-immunoreactive nerve fiber (red) in the hepatic portal space of a rat with counterstained macrophages (green). Note red-fluorescent cells which likely represent cholinergic lymphocytes. c-e: 3D projection images obtained with light sheet microscope from cleared, whole-mounted right lateral lobe of mouse liver lobe showing dense innervation that follows blood vessels deep into hepatic parenchyma, visualized by the pan-neuronal marker PGP 9.5 (c), and tyrosine hydroxylase (TH, d) immunohistochemistry, but absence of cholinergic innervation visualized by vesicular acetylcholine transporter (VAChT) immunohistochemistry (e). With permission from Liu K et al.(Liu et al., 2021). Scale bars: a, 20 μm; b, 100 μm; c-e, 1 mm.

Fig. 5.. Sensory neural pathways from the liver to the brain.

Highly schematic diagram of vagal (green) and spinal (red) sensory pathways, with sensors in the liver area and projections to various brain areas. Note that the stomach and intestinal tract are not shown for clarity. Abbreviations periphery: ac, celiac artery; agd, gastroduodenal artery; ags, left gastric artery; aahc, common hepatic artery; ahe, hepatoesophageal artery; ahp, hepatic artery proper; al, splenic artery; ams, superior mesenteric artery; DRG, dorsal root ganglion; Th7-Th13, thoracic spinal cord segments. Abbreviations brain: Acb, nucleus accumbens; ACC, anterior cingulate cortex; Amy, amygdala; DMX, dorsal motor nucleus of the vagus; DSTR, dorsal striatum; HIP, hippocampus; Ins, insular cortex; LHA, lateral hypothalamus; NTS, nucleus tractus solitarius; PAG, periaqueductal grey; PBN, parabrachial nucleus; VLM, ventrolateral medulla; VTA, ventral tegmental area.