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

Jung-Yeon Kim,Jaechan Leem,Gyun-Moo Kim,Hyo-Jeong Jang

doi:10.3390/biomedicines9080992

Abstract

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.

Highlights

Cholestatic liver diseases such as primary sclerosing cholangitis and primary biliary cholangitis are a significant cause of liver-related death and the leading indication for liver transplantation in pediatric patients [1,2]
We found that increased protein levels of TGF-β1 and phosphorylated results suggest that suppression of TGF-β/Smad2/3 signaling pathway by bee venom-derived secretory PLA2 (sPLA2) (bvPLA2), at least in part, contributes to its inhibitory effect on fibrosis
We demonstrated that administration ofameliorated bvPLA2 ameliorated the DDC diet-induced demonstrated that administration of bvPLA2 the DDC diet-induced cholestatic liver injury and fibrosis through suppressing apoptosis and inflammatory responses

Summary

Introduction

Cholestatic liver diseases such as primary sclerosing cholangitis and primary biliary cholangitis are a significant cause of liver-related death and the leading indication for liver transplantation in pediatric patients [1,2]. Cholestasis induces hepatic injury and fibrosis [3]. The exact mechanisms are not yet fully understood, apoptotic cell death and inflammation are critically involved in cholestatic liver diseases [3,4]. Bee venom therapy has long been used for the therapy of various human diseases, especially in Asia [5,6]. Bee venom is a complex mixture of peptides, enzymes, and other bioactive components. Many of the mechanisms of action still remain unclear, accumulating evidence suggests that bee venom-derived sPLA2 (bvPLA2)

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