Shi Qiaoli, Wang Qixin, Chen Jiayun, Xia Fei, Qiu Chong, Li Min, Zhao Minghong, Zhang Qian, Luo Piao, Lu Tianming, Zhang Ying, Xu Liting, He Xueling, Zhong Tianyu, Lin Na, Guo Qiuyan
Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2022 Feb 14;12:822154. doi: 10.3389/fphar.2021.822154. eCollection 2021.
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. We assumed that GA could relieve TGT-induced acute liver injury by regulating liver function-related genes and lipid metabolites. TGT-induced acute liver injury models were constructed and . Then the liver protective effect and mechanisms of GA were investigated by a combination of transcriptome, lipid metabolomics, and experimental validation. 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 and . 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 results indicated that pre-administration of GA markedly alleviated the inhibitory effect of TGT on BRL-3A activity. 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.
据报道，甘草酸（GA）具有肝脏保护作用；然而，GA对雷公藤多苷片（TGT）诱导的急性肝损伤的特征及潜在机制仍未阐明。我们推测GA可通过调节肝功能相关基因和脂质代谢产物来减轻TGT诱导的急性肝损伤。构建了TGT诱导的急性肝损伤模型，然后通过转录组学、脂质代谢组学和实验验证相结合的方法研究GA的肝脏保护作用及其机制。预先连续6天腹腔注射GA。然后，除正常组外，通过单次口服270 mg/kg的TGT构建TGT诱导的急性肝损伤模型。18小时后处死所有动物。定量检测血清中天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、碱性磷酸酶（ALP）、总胆红素（TBIL）、谷胱甘肽过氧化物酶（GSH-PX）和超氧化物歧化酶（SOD）的水平。用苏木精-伊红（HE）染色观察肝组织病理变化，并选取肝组织进行转录组和代谢组测序。分析并进一步验证其潜在机制。预先给予GA可显著降低AST、ALT、ALP和TBIL的血清浓度，但可提高SOD和GSH-Px的血清浓度，改善TGT诱导的急性肝损伤小鼠的肝脏形态。此外，GA可显著提高Cyp2b13、Cyp2c69、Cyp3a16、Cyp3a44、Fmo3和Nipal1的基因水平。筛选出差异积累的代谢产物，并归类为磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）。结果表明，预先给予GA可显著减轻TGT对BRL-3A活性的抑制作用。本研究结合转录组学、脂质代谢组学和实验验证，提供了令人信服的证据，证明GA通过调节CYP活性以及PC和PE的代谢，部分减轻了TGT诱导的急性肝损伤。
