非酒精性脂肪性肝病(NAFLD)是肝脏总胆固醇(TC)和总甘油三酯(TG)积累增加的结果。在我们之前的研究中,我们发现用金丝桃苷治疗的大鼠对肝脏脂质积累产生了抗性。
本研究旨在研究金丝桃苷对NAFLD大鼠肝脏组织脂质积累的抑制作用的可能机制。
应用针对胆汁酸(BA)代谢的无标记蛋白质组学和代谢组学,以揭示金丝桃苷减少NAFLD大鼠肝脂质积累的机制。
为了应对金丝桃苷治疗,与脂肪酸降解途径相关的几种蛋白质,胆固醇代谢途径,胆汁分泌途径发生了改变,包括ECI1,Acnat2,ApoE,和BSEP,等。核受体(NRs)的表达,包括法尼醇X受体(FXR)和肝X受体α(LXRα),在金丝桃苷治疗的大鼠肝脏组织中增加,伴随着肝脏从头脂肪生成中催化酶的蛋白质表达减少,以及经典和替代BA合成途径中酶的蛋白质水平增加。肝缀合的BAs比未缀合的BAs毒性更小并且更亲水。BA靶向代谢组学表明,金丝桃苷可以降低肝脏未结合BA的水平,并增加肝脏结合BA的水平。
合照,结果表明,金丝桃苷可以通过调节胆固醇代谢以及BAs的代谢和排泄来改善NAFLD的状况。这些发现有助于理解金丝桃苷降低NAFLD大鼠胆固醇和甘油三酯的机制。
Non-alcoholic fatty liver disease (NAFLD) results from increased hepatic total cholesterol (TC) and total triglyceride (TG) accumulation. In our previous study, we found that rats treated with hyperoside became resistant to hepatic lipid accumulation.
The present study aims to investigate the possible mechanisms responsible for the inhibitory effects of hyperoside on the lipid accumulation in the liver tissues of the NAFLD rats.
Label-free proteomics and metabolomics targeting at bile acid (BA) metabolism were applied to disclose the mechanisms for hyperoside reducing hepatic lipid accumulation among the NAFLD rats.
In response to hyperoside treatment, several proteins related to the fatty acid degradation pathway, cholesterol metabolism pathway, and bile secretion pathway were altered, including ECI1, Acnat2, ApoE, and BSEP, etc. The expression of nuclear receptors (NRs), including farnesoid X receptor (FXR) and liver X receptor α (LXRα), were increased in hyperoside-treated rats\' liver tissue, accompanied by decreased protein expression of catalyzing enzymes in the hepatic de novo lipogenesis and increased protein level of enzymes in the classical and alternative BA synthetic pathway. Liver conjugated BAs were less toxic and more hydrophilic than unconjugated BAs. The BA-targeted metabolomics suggest that hyperoside could decrease the levels of liver unconjugated BAs and increase the levels of liver conjugated BAs.
Taken together, the results suggest that hyperoside could improve the condition of NAFLD by regulating the cholesterol metabolism as well as BAs metabolism and excretion. These findings contribute to understanding the mechanisms by which hyperoside lowers the cholesterol and triglyceride in NAFLD rats.