Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1.

Lu Xiao-Rong,Liu Xi-Wang,Li Jian-Yong,Yang Ya-Jun,Bai Li-Xia,Li Shi-Hong,Ma Ning,Qin Zhe

doi:10.3389/fphar.2021.733789

Abstract

Hyperlipidemia is an important lipid disorder and a risk factor for health. Aspirin eugenol ester (AEE) is a novel synthetic compound which is made up of two chemical structural units from aspirin and eugenol. Therapeutic effect of AEE on hyperlipidemia has been confirmed in animal model. But the action mechanism of AEE on hyperlipidemia is still poorly understood. In this study, we investigated the effects of AEE on liver and feces metabolic profile through UPLC-Q-TOF/MS-based untargeted metabolomics in hyperlipidemia hamster induced with high fat diet (HFD), and the effects of AEE on the expression of genes and proteins related to cholesterol and bile acid (BA) in HFD-induced hyperlipidemia SD rat. The concentrations of 26 bile acids (BAs) in the liver from hyperlipidemia SD rat were also quantified with the application of BA targeted metabolomics. The results of untargeted metabolomics showed that the underlying mechanism of AEE on hyperlipidemia was mainly associated with amino acid metabolism, glutathione metabolism, energy metabolism, BA metabolism, and glycerophospholipid metabolism. AEE induced the expression of the BA-synthetic enzymes cholesterol 7α-hydroxylase (CYP7A1) by the inhibition of BA nuclear receptor farnesoid X receptor (FXR) in liver, which resulted in accelerating the conversion of cholesterol into bile acids and excrete in feces. The results of BA targeted metabolomics showed that AEE elevated the glycine-conjugated BA level and decreased the tauro-conjugated BA level. In conclusion, this study found that AEE decreased FXR and increased CYP7A1 in the liver, which might be the possible molecular mechanisms and targets of AEE for anti-hyperlipidemia therapies.

Highlights

As a multi-factorial disease, hyperlipidemia has been becoming a non-negligible health problem and is considered to be one of the main causes of cardiovascular disease (CVD) (Bonora, 2006; Prasun, 2020)
The metabolic profile of hamster in Aspirin eugenol ester (AEE) group fairly differed from the model group, suggesting that the deviations induced by hyperlipidemia were significantly improved after AEE treatment
In high fat diet (HFD) and HFD + AEE group, the results revealed that the levels of glycineconjugated bile acid (BA), hyodeoxycholic acid (HDCA), taurocodeoxycholic acid (TDCA), taurolithocholic acid (TLCA), apocholic acid (ApoCA), and 3dehydrocholic acid/3-oxocholic acid (3-DHCA) were dramatically elevated and isolithocholic acid (IsoLCA), cholic acid (CA), and IsoLCA were significantly decreased after AEE treatment

Summary

Introduction

As a multi-factorial disease, hyperlipidemia has been becoming a non-negligible health problem and is considered to be one of the main causes of cardiovascular disease (CVD) (Bonora, 2006; Prasun, 2020). CVD is a leading cause of death, and the blood lipids play a critical role in diagnosis and treatment of hyperlipidemia and CVD (Karr, 2017). The accumulation of serum lipids in blood stream and liver is the main cause of hyperlipidemia, and the recovery of serum lipids is the leading part in hyperlipidemia treatment. Synthesis and excretion of BA play important roles in cholesterol and lipid metabolism, which are closely related to hyperlipidemia (Cerqueira et al, 2016). The main production of the classical or neutral pathway catalyzed by CYP7A1 and oxysterol 12 α-hydroxylase (CYP8B1) is cholic acid (CA). The alternative acidic pathway is catalyzed by sterol-27α hydroxylase (CYP27A1) and oxysterol 7α-hydroxylase (CYP7B1), and the main production is chenodeoxycholic acid (CDCA) (Thomas et al, 2008; Chiang, 2009; Chambers et al, 2019). The BAs can combine with glycine and taurine to form conjugated BA such as glycine-conjugated BAs (G-BAs) and taurine-conjugated BAs (T-BAs) (Schwarz et al, 1996), and most of BAs return to liver from the portal vein and a part of them is excreted in feces (Li-Hawkins et al, 2002; Chiang, 2009)

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Conclusion