Protective Effects of Bee Venom-Derived Phospholipase A₂ against Cholestatic Liver Disease in Mice

Hepatocyte apoptosis and inflammation play important roles in cholestatic liver diseases. Bee venom-derived secretory phospholipase A2 (bvPLA2) has been shown to ameliorate various inflammatory diseases. However, whether bvPLA2 has a therapeutic effect against cholestatic liver disease has not been evaluated. Therefore, we investigated the effects of bvPLA2 on cholestatic liver injury and fibrosis in a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding. The administration of bvPLA2 ameliorated liver damage, cholestasis, and fibrosis in DDC diet-fed mice, as assessed by serum biochemical tests and histological examinations. In addition, bvPLA2 reduced myofibroblast accumulation, concomitant with suppression of transforming growth factor-β signaling cascade. The administration of bvPLA2 inhibited hepatocyte apoptosis in DDC diet-fed mice as represented by a reduction in the number of cells stained with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and suppression of caspase-3 activation. Moreover, bvPLA2 reduced cytokine production along with the inhibition of the nuclear factor kappa-B pathway. The number of regulatory T-cells was increased by bvPLA2, while the number of other immune cells, including neutrophils, macrophages, and CD8⁺ T-cells, was decreased. Our data indicate that the administration of bvPLA2 ameliorates cholestatic liver injury and fibrosis by inhibiting hepatocyte apoptosis and inflammation.