Transcriptome and Lipid Metabolomics-Based Discovery: Glycyrrhizic Acid Alleviates Tripterygium Glycoside Tablet-Induced Acute Liver Injury by Regulating the Activities of CYP and the Metabolism of Phosphoglycerides

Qiaoli Shi; Qixin Wang; Jiayun Chen; Fei Xia; Chong Qiu; Min Li; Minghong Zhao; Qian Zhang; Piao Luo; Tianming Lu; Ying Zhang; Liting Xu; Xueling He; Tianyu Zhong; Na Lin; Qiuyan Guo

doi:10.3389/fphar.2021.822154

Transcriptome and Lipid Metabolomics-Based Discovery: Glycyrrhizic Acid Alleviates Tripterygium Glycoside Tablet-Induced Acute Liver Injury by Regulating the Activities of CYP and the Metabolism of Phosphoglycerides

Front Pharmacol. 2022 Feb 14:12:822154. doi: 10.3389/fphar.2021.822154. eCollection 2021.

Authors

Qiaoli Shi¹, Qixin Wang¹, Jiayun Chen¹, Fei Xia¹, Chong Qiu¹, Min Li², Minghong Zhao^{1

3}, Qian Zhang¹, Piao Luo¹, Tianming Lu¹, Ying Zhang¹, Liting Xu¹, Xueling He¹, Tianyu Zhong^{3

4}, Na Lin¹, Qiuyan Guo¹

Affiliations

¹ Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
² China Academy of Chinese Medical Sciences, Beijing, China.
³ Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China.
⁴ Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.

Abstract

Background: Glycyrrhizic acid (GA) has been reported to be liver protective; however, the characters and underlying mechanisms of GA against tripterygium glycoside tablet (TGT)-induced acute liver injury remain unelucidated. Hypothesis/Purpose: We assumed that GA could relieve TGT-induced acute liver injury by regulating liver function-related genes and lipid metabolites. Study Design: TGT-induced acute liver injury models were constructed in vivo and in vitro. Then the liver protective effect and mechanisms of GA were investigated by a combination of transcriptome, lipid metabolomics, and experimental validation. Methods: Intraperitoneal injection of GA was given in advance for six successive days. Then, the TGT-induced acute liver injury model was constructed by a single oral administration of TGT at 270 mg/kg, except for the normal group. All animals were sacrificed 18 h later. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) were quantified. Liver tissues were used to observe pathological changes through hematoxylin-eosin (HE) staining and selected for transcriptome and metabolome sequencing. The underlying mechanisms were analyzed and further validated both in vivo and in vitro. Results: Pre-administration of GA markedly decreased the serum concentrations of AST, ALT, ALP, and TBIL but increased those of SOD and GSH-Px, improving the liver morphology of mice with TGT-induced acute liver injury. In addition, GA significantly increased the gene levels of Cyp2b13, Cyp2c69, Cyp3a16, Cyp3a44, Fmo3, and Nipal1. Differentially accumulated metabolites were screened and classified as phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The in vitro results indicated that pre-administration of GA markedly alleviated the inhibitory effect of TGT on BRL-3A activity. Conclusion: This study combined transcriptome, lipid metabolomics, and experimental validation to offer convincing evidence that GA alleviates TGT-induced acute liver injury partially by regulating the activities of CYP and the metabolism of PC and PE.

Keywords: glycyrrhizic acid; lipid metabolomics; liver injury; transcriptome; tripterygium glycoside tablet.