Retinoic Acid Attenuates Sepsis-Induced Liver Injury Via RIG-I Inhibition-Mediated Suppression of TNF-α/RIPK1/RIPK3/MLKL Pathway.

BACKGROUND

Sepsis-induced liver injury affects about 34.7% of patients and correlates with prognosis. Although vitamin A (VA) and retinol-binding protein 4 [RBP4] are reduced in sepsis, the protective role of VA remains unknown. This study aimed to explore the effects of VA and mechanisms in septic liver injury.

METHODS

Cecal ligation puncture was performed in male C57BL/6 mice. After 24 hours, retinol (ROL, 0.01, 0.1, 1 mg/kg), RBP4 (0.5 mg/kg), or their combinations were administered. Liver/serum samples collected 24 hours later assessed injury (histopathology, function) and retinoic acid (RA)-inducible gene-I (RIG-I)/ receptor-interacting protein kinase (RIPK)1/RIPK3/mixed lineage kinase domain-like protein (MLKL) expression via immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction. In lipopolysaccharide (LPS)-stimulated alpha mouse liver-12 cells, ROL, RBP4, ROL+RBP4, or RA effects were evaluated.

RESULTS

Cecal ligation puncture mice showed decreased serum ROL at 12 hours (lowest at 24 hours), while RBP4 transiently rose at 3 hours before declining (lowest at 24 hours). ROL (1 mg/kg) + RBP4 significantly improved survival, reduced liver injury (low Knodell scores), and suppressed RIG-I/TNF-α/RIPK1-RIPK3-MLKL necroptosis. LPS reduced RBP4 in alpha mouse liver-12 cells ( P < 0.001); ROL + RBP4 and RA alleviated damage via inhibiting necroptosis.

CONCLUSIONS

VA may exert hepatoprotection by suppressing RIG-I, reducing tumor necrosis factor-α, and inhibiting RIPK1/RIPK3/MLKL-mediated necroptosis.