Introduction: 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.
Objectives: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: ACC, Acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; Apo, apolipoprotein; BAs, bile acids; BSH, bile salt hydrolase; Bile acid metabolism; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; Cholesterol metabolism; FGF15/19, fibroblast growth factor 15/19; FXR, farnesoid X receptor; Hyperoside; LC-MS, the combination of high-performance liquid chromatography and mass spectrometry; LXRα, liver X receptor α; Label-free proteomics; NAFLD; NAFLD, non-alcoholic fatty liver disease; PMSF, phenylmethylsulfonyl fluoride; QC, quality control; SDS, sodium dodecyl sulfate; SHP, small heterodimer partner; SREBP1, sterol regulatory element-binding protein 1; SREBP2, sterol regulatory element-binding protein 2; SREBPs, sterol regulatory element binding proteins; TC, total cholesterol; TG, triglyceride; TGR5, Takeda G-protein-coupled receptor 5; Targeted metabolomics; VLDL, very low-density lipoprotein; WB, Western blot; pACC, phosphorylated ACC.
© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).