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Hepatoprotective effects of resolvin D1 in mice exposed to ethanol and galactosamine
Josiah Hardesty1,2, Jeffrey Warner1,2, Dennis Warner1
1Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky, USA.
Background:
Alcohol-associated liver disease (ALD) is a major global health condition characterized by inflammation, hepatocellular injury, fibrosis, and impaired liver regeneration. To capture key features of severe ALD, we employed a murine model combining ethanol (EtOH) exposure with galactosamine (GalN), a hepatotoxic agent that sensitizes the liver to endotoxin-induced injury. Using this model, we evaluated the therapeutic efficacy of resolvin D1 (RvD1), a lipid mediator with potent anti-inflammatory and tissue-protective actions.
Methods:
C57BL/6J male mice were fed 5% EtOH-containing liquid diet for 10 days and administered GalN (500 mg/kg, i.p.) on days 9, 10, and 11, followed by a single EtOH binge (5 g/kg) on day 11. A separate cohort also received RvD1 (500 ng/mouse, days 7-12) as a therapy. Markers of endotoxemia, liver injury, inflammation, fibrosis, and regeneration were evaluated at 9 and 48 hours after the binge.
Results:
The EtOH+GalN model reproduced hallmark features of advanced ALD, including acute liver injury, sustained inflammation, induction of pro-fibrotic gene markers, reduced hepatic synthetic function, and markedly impaired regenerative capacity. RvD1 treatment significantly mitigated EtOH+GalN-induced pathology, lowering plasma endotoxin and ALT levels, reducing hepatic necrosis, and limiting neutrophil infiltration. RvD1 also decreased hepatic IL-6 levels at 9 hours and reduced IFN-γ at 48 hours. In addition, RvD1 attenuated the expression of pro-fibrotic genes and improved the diminished regenerative response in EtOH+GalN-treated mice, increasing hepatocyte proliferation at 48 hours and partially restoring plasma albumin concentrations.
Conclusion:
This study established an EtOH+GalN exposure mouse model of severe ALD and demonstrated that RvD1 exerts significant hepatoprotective effects. The findings support RvD1 as a promising therapeutic candidate for advanced ALD and provide the rationale for further mechanistic studies and translational evaluation.