Hepatic Injury Mechanisms in Cholestatic Liver Disease

Cholestatic liver disease arises when bile flow is disrupted, leading to intrahepatic accumulation of bile acids that exert direct cytotoxic effects on hepatocytes. These amphipathic molecules induce mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress, triggering hepatocyte apoptosis and necrosis. Injured hepatocytes release danger‐associated molecular patterns that activate resident macrophages (Kupffer cells) and recruit circulating immune cells, perpetuating inflammation. Proinflammatory cytokines and chemokines promote transdifferentiation of quiescent hepatic stellate cells into myofibroblast‐like cells that synthesise extracellular matrix proteins, notably collagen, driving periductal and perisinusoidal fibrosis. Key signalling cascades include HMGB1/RAGE‐mediated NF-κB and JNK activation, TGF-β-SMAD pathways and p38 MAPK signalling. Progression to cirrhosis involves microvascular remodelling, cholangiocyte proliferation and portal hypertension. Genetic predisposition and alterations in bile acid transporters modulate susceptibility. Understanding these interconnected pathways is critical to devising therapies that attenuate injury, suppress fibrogenesis and promote regeneration.

Research from Nature Portfolio

Recent studies have identified novel antifibrotic strategies in experimental cholestasis. An interleukin-1β inhibitor was shown to protect against bile‐duct-ligation-induced fibrosis by attenuating oxidative stress and endoplasmic reticulum stress, down‐regulating HMGB1/RAGE-NF-κB/JNK signalling and reducing expression of fibrogenic mediators such as TGF-β1 and α-smooth muscle actin. This treatment also preserved hepatocyte architecture and suppressed apoptosis. In a complementary line of investigation, recombinant human cytoglobin demonstrated potent cytoprotective effects in a carbon tetrachloride model, restoring serum transaminase levels, diminishing collagen deposition and modulating proteins involved in oxidative stress pathways. These findings underscore the therapeutic potential of targeting reactive oxygen species and stress-response pathways to mitigate cholestatic injury.

Hepatic Injury Mechanisms in Cholestatic Liver Disease publication trend

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

Technical terms

Cholestasis: Impaired bile flow causing intrahepatic bile acid retention.

Hepatic stellate cell: Perisinusoidal cell that transdifferentiates into a collagen‐producing myofibroblast upon injury.

Bile acids: Amphipathic molecules that aid digestion but are hepatotoxic at high concentrations.

Oxidative stress: Imbalance between reactive oxygen species production and antioxidant defences.

Endoplasmic reticulum stress: Accumulation of misfolded proteins in the ER triggering the unfolded protein response.

Fibrosis: Excessive deposition of extracellular matrix in response to chronic injury.

HMGB1/RAGE pathway: Inflammatory signalling axis involving high‐mobility group box 1 and its receptor, driving NF-κB activation.

References

1. Diacerein ameliorates cholestasis-induced liver fibrosis in rat via modulating HMGB1/RAGE/NF-κB/JNK pathway and endoplasmic reticulum stress. Scientific Reports (2023).
2. The Effect of rhCygb on CCl4-Induced Hepatic Fibrogenesis in Rat. Scientific Reports (2016).
3. GSK805 inhibits alpha‐smooth muscle expression and modulates liver inflammation without impairing the well‐being of mice. The FASEB Journal (2024).
4. Ursodesoxycholic acid alleviates liver fibrosis via proregeneration by activation of the ID1‐WNT2/HGF signaling pathway. Clinical and Translational Medicine (2021).
5. Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation.. Journal of Cellular Signaling (2021).