Hepatic Nervous System Interactions in Liver Disease

The liver is densely innervated by autonomic and sensory fibres that modulate metabolic, immune and regenerative processes. Parasympathetic signals transmitted via the vagus nerve and sympathetic outputs from spinal pathways converge on hepatocytes, non-parenchymal cells and resident immune populations. This neural dialogue influences lipid handling, inflammatory cytokine release and activation of hepatic stellate cells, which are central mediators of fibrosis. Neural inputs can either protect against or exacerbate disease, depending on the balance between cholinergic, adrenergic and peptidergic signalling. In conditions such as non-alcoholic steatohepatitis and cirrhosis, alterations in neuroimmune cross-talk drive maladaptive programmes of extracellular matrix deposition, oxidative stress and cell death. At the same time, central circuits in the brainstem and hypothalamus sense nutrient and hormone levels, relaying modulatory signals via the vagus nerve to regulate hepatic lipid export, gluconeogenesis and fibrogenesis. Understanding these bidirectional axes has unveiled novel opportunities to target neural receptors or stimulate defined nerve pathways for therapeutic benefit. Emerging strategies include pharmacological agonists and antagonists of neurotransmitter receptors, as well as bioelectronic modulation of autonomic outflow to restore homeostatic liver function and limit disease progression.

Research from Nature Portfolio

Recent studies have shown that central leptin action in the dorsal vagal complex protects against hepatic steatosis by enhancing triglyceride export and suppressing new lipid synthesis, an effect that depends on intact vagal innervation of the liver. In parallel, investigations of human hepatic stellate cells have revealed that these cells produce and respond to neuropeptide Y via the Y1 receptor, driving fibrogenic signalling through mTOR and downstream effectors. Blockade of the Y1 receptor attenuates stellate cell activation, highlighting a neural peptide axis that contributes to liver scarring.

Hepatic Nervous System Interactions in Liver Disease publication trend

The graph below shows the total number of articles in hepatic nervous system interactions in liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatic stellate cells: Perivascular cells in the liver that, upon activation by injury or inflammation, transdifferentiate into myofibroblast-like cells and drive extracellular matrix production.

Cholinergic signalling: Neurotransmission mediated by acetylcholine acting on nicotinic or muscarinic receptors to regulate cellular functions.

Vagus nerve: The tenth cranial nerve conveying parasympathetic efferent and visceral afferent signals between the brainstem and abdominal organs, including the liver.

Dorsal vagal complex: A brainstem nucleus that integrates visceral sensory information and orchestrates autonomic outputs through the vagus nerve.

Neuropeptide Y (NPY): A peptide neurotransmitter released by sympathetic fibres that influences cell proliferation, inflammation and fibrogenesis.

Fibrosis: Pathological accumulation of collagen and other extracellular matrix components leading to tissue scarring and impaired organ function.

CHRNA2: A subunit of the nicotinic acetylcholine receptor found on hepatocytes, mediating protective cholinergic responses to metabolic stress.

References

1. Signaling through the nicotinic acetylcholine receptor in the liver protects against the development of metabolic dysfunction-associated steatohepatitis. PLOS Biology (2024).
2. Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation. Bioelectronic Medicine (2023).
3. Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity. Annals of Medicine (2023).
4. Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis. Nature Communications (2019).
5. Sympathetic Nervous System Catecholamines and Neuropeptide Y Neurotransmitters Are Upregulated in Human NAFLD and Modulate the Fibrogenic Function of Hepatic Stellate Cells. PLOS ONE (2013).