Oridonin alleviates hyperbilirubinemia through activating LXRα-UGT1A1 axis

作者：Zhan, Zhikun; Dai, Fahong; Zhang, Tao; Chen, Yulian; She, Jianglian; Jiang, Huanguo; Liu, Shuwen; Gu, Tanwei; Tang, Lan^*

来源：Pharmacological Research, 2022, 178: 106188.

DOI：10.1016/j.phrs.2022.106188

• Hyperbilirubinemia
• Oridonin
• LXR alpha
• UGT1A1
• Bilirubin

Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXR alpha) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXR alpha acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXR alpha and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXR alpha-/- mice. Ori or LXR agonist GW3965 also reduced lipopolysaccharide/D-galactosamine-induced hyperbilirubinemia via activating LXR alpha/UGT1A1 in WT mice. Liver UGT1A1 enzyme activity was elevated by Ori or GW3965 in WT mice. Further, Ori up-regulated LXR alpha gene expression, increased its nuclear translocation and stimulated UGT1A1 promoter activity in HepG2 cells. After silencing LXR alpha by siRNA, Ori-induced UGT1A1 expression was markedly reduced in HepG2 cells and primary mouse hepatocytes. Taken together, Ori stimulated the transcriptional activity of LXR alpha, resulting in the up-regulation of UGT1A1. Therefore, Ori or its analogs might have the potential to treat hyperbilirubinemia-related diseases through modulating LXR alpha-UGT1A1 signaling.

• 单位
  中国科学院; 南方医科大学