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Retinoic Acid Attenuates Sepsis-Induced Liver Injury Via RIG-I Inhibition-Mediated Suppression of
Maoxia Liu1, Qinyi Fu, Xuepeng Zhang
1Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China.
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.
