Nitric Oxide Dynamics in Liver Disease

Nitric oxide (NO) functions as both a critical signalling molecule and a potential mediator of injury within the liver. In healthy tissue, endothelial nitric oxide synthase (eNOS) generates basal NO to regulate sinusoidal blood flow, maintain microvascular tone and support mitochondrial health. In inflammatory settings, inducible nitric oxide synthase (iNOS) can flood the parenchyma with high NO concentrations, modulating cytokine release and cell survival. Dysregulated NO production contributes to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), steatohepatitis, ischaemia–reperfusion injury following transplantation and fibrotic progression. On one hand, physiologically low NO levels preserve sinusoidal perfusion and quench reactive oxygen species; on the other hand, excessive NO can react with superoxide to form peroxynitrite, leading to protein nitration, mitochondrial dysfunction and cell death. Recent insights have unveiled mechanisms by which dietary cues alter NO-dependent S-nitrosylation of metabolic enzymes, while pharmacological agents modulate iNOS expression to attenuate inflammation. A deeper understanding of NO’s dualistic roles offers avenues for biomarker development and targeted therapies aimed at restoring NO homeostasis and protecting hepatic function across a spectrum of global liver disorders.

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Nitric Oxide Dynamics in Liver Disease publication trend

The graph below shows the total number of articles in nitric oxide dynamics in liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Endothelial nitric oxide synthase (eNOS): An enzyme constitutively expressed in endothelial and hepatic cells that produces NO at low levels to regulate vascular tone and mitochondrial function.

Inducible nitric oxide synthase (iNOS): An enzyme upregulated by inflammatory stimuli that generates high NO fluxes, influencing cytokine cascades and oxidative stress.

S-nitrosylation: A reversible post-translational modification in which an NO moiety is covalently bound to a protein cysteine residue, altering enzyme activity or signalling.

Peroxynitrite: A reactive nitrogen species formed by the rapid reaction of NO with superoxide, capable of nitrating proteins and inducing cellular injury.

Non-alcoholic fatty liver disease (NAFLD): A spectrum of metabolic liver disorders characterised by excess lipid accumulation in hepatocytes, ranging from steatosis to steatohepatitis and fibrosis.

References

1. Activation of hepatic acetyl-CoA carboxylase by S-nitrosylation in response to diet. Journal of Lipid Research (2024).
2. Olprinone, a Selective Phosphodiesterase III Inhibitor, Has Protective Effects in a Septic Rat Model after Partial Hepatectomy and Primary Rat Hepatocyte. International Journal of Molecular Sciences (2024).
3. Characterization of hepatic fatty acids using magnetic resonance spectroscopy for the assessment of treatment response to metformin in an eNOS−/− mouse model of metabolic nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. NMR in Biomedicine (2023).
4. The Emerging Role of Hepatocellular eNOS in Non-alcoholic Fatty Liver Disease Development. Frontiers in Physiology (2020).
5. Functional Roles of Protein Nitration in Acute and Chronic Liver Diseases. Oxidative Medicine and Cellular Longevity (2014).