Tormentic Acid Ameliorates Hepatic Fibrosis in vivo by Inhibiting Glycerophospholipids Metabolism and PI3K/Akt/mTOR and NF-κB Pathways: Based on Transcriptomics and Metabolomics.

Xing Lin,Quanfang Huang,Quanfang Huang,Jinbin Wei,Yuanyuan Wei,Renbin Huang,Bin Fang,Yuhua Xiong,Cuiyu Li,Yan Li

doi:10.3389/fphar.2022.801982

Abstract

This study aimed to investigate the effects and underlying mechanisms of tormentic acid (TA) on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. The rats were intragastrically administered with 50% CCl4 for 9 weeks to induce hepatic fibrosis, followed by various agents for 6 weeks. Transcriptomic analysis was carried out to predict the potential targets, and then multiple examinations were performed to verify the prediction. The results showed that TA significantly alleviated liver injury and fibrosis, as evidenced by the ameliorative pathological tissue, low transaminase activity, and decreased collagen accumulation. Besides, TA markedly reduced hepatocyte apoptosis by regulating the expression of caspase-3 and Bcl-2 families. The transcriptomic analysis revealed 2,173 differentially expressed genes (DEGs) between the TA and model groups, which could be enriched in the metabolic pathways and the PI3K/Akt and NF-κB signaling pathways. The metabolomics analysis showed that TA could regulate the glycerophospholipid metabolism pathway by regulating the synthesis of phosphatidylserines, phosphatidylethanolamines and phosphatidylcholines. Moreover, the integrative analysis of the transcriptomics and metabolomics data indicated that TA inhibited the glycerophospholipid metabolism pathway by inhibiting the expression of LPCAT4, PTDSS2, PLA2G2A and CEPT1. In addition, the relevant signaling pathways analysis confirmed that TA inhibited HSCs activation by blocking the PI3K/Akt/mTOR pathway and ameliorated inflammatory injury by inhibiting the NF-κB pathway. In conclusion, TA significantly alleviates liver fibrosis in vivo by inhibiting the glycerophospholipid metabolism pathway and the PI3K/Akt/mTOR and NF-κB signaling pathways.

Highlights

Liver fibrosis caused by various chronic stimuli, such as viruses, alcohol, and autoimmune diseases, is a reversible pathological process
CCl4 exposure caused a significant increase in ALT, AST, and total bilirubin (TBIL), while a decrease in ALB (Figure 1B); colchicine or tormentic acid (TA) treatment markedly reversed these abnormal changes, suggesting that TA could improve hepatic function
The analysis indicated that there were 2,173 differentially expressed genes (DEGs) between the TA and model groups, and these DEGs could be functionally annotated in the liver fibrosisrelated pathways, including the metabolic pathways, PI3K/Akt signaling pathway, ECM formation, and NF-κB signaling pathway

Summary

Introduction

Liver fibrosis caused by various chronic stimuli, such as viruses, alcohol, and autoimmune diseases, is a reversible pathological process. It is urgent to develop diagnostic techniques and new agents to prevent liver fibrosis progression. Multi-omics analysis has been considered a useful tool to study the pathogenesis of various diseases and drug discovery because of its advantage in providing insight into the potential biomarkers and mechanism as a whole. Transcriptome analysis can detect the complete set of RNA transcripts, which is helpful to expose the molecular mechanisms of the anti-hepatic fibrosis drugs (Zhang et al, 2019). Metabolomics analysis can provide the global metabolic profile and identify the differently expressed metabolites. The integrative analysis of transcriptome and metabolome has been increasingly used to investigate the complicated mechanisms of liver diseases (Zhao et al, 2020; Tang et al, 2021)

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