Triterpenoids from ilicis rotundae cortex ameliorate hyperlipidemia by affecting bile acids-hepatointestinal FXR axis

Abstract

Background

Hyperlipidemia is a lipid metabolism disorder that, in severe cases, can lead to conditions such as hypertension, coronary heart disease, and cirrhosis. Previous studies have identified Ilicis Rotundae Cortex (IRC) crude extract as having the potential to regulate blood lipids. However, whether the triterpenoids therein are the principal agents responsible for hypolipidemic effects and their specific mechanisms of action remain unexplored. This study aimed to investigate the effects of total triterpenoids (TT) extract derived from IRC on hyperlipidemia and to elucidate their potential mechanisms.

Methods

TT extract was first prepared and characterized to assess their hypolipidemic activity in cell models. A hyperlipidemia mouse model was established by using C57BL/6 J mice fed a high-fat, high-sugar, and high-cholesterol diet for 8 weeks. TT extract was administered as a prophylactic intervention for 4 weeks to evaluate its impact on blood lipid levels, liver lipid metabolism, and liver function. Based on progressive analysis, this study integrated serum non-targeted metabolomics analysis strategy and bile acids-targeted metabolomics analysis strategy. It was combined with modern molecular biology techniques to reveal the mechanism by which TT extract ameliorated the symptoms of hyperlipidemia through a cascade approach.

Results

TT extract treatment significantly reduced lipid levels in hyperlipidemic mice. Notably, TT extract down-regulated bile acid levels, particularly bile acids as FXR antagonists such as T-β-MCA, β-MCA, TUDCA, and UDCA. This effect is likely mediated through alterations in the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways. TT extract administration led to decreased expression of CYP7A1 and CYP7B1, resulting in reduced bile acid levels in vivo. Additionally, FXR expression was upregulated in both the liver and ileum, potentially activating FGF15 in the ileum, which in turn transmits signals to the liver and modulates SHP and BSEP expression. These changes contribute to the regulation of bile acid synthesis, metabolism, and excretion. In vitro experiments also demonstrated that TT extract influenced the protein expression of FXR and FGF19.

Conclusion

Our findings demonstrate that TT extract from IRC has hypolipidemic effects. This study is the first to reveal the mechanism by which TT extract improves hyperlipidemia from the perspective of the hepatic-intestinal axis and bile acid metabolism. Its underlying mechanism is related to activating the intestinal FXR-FGF15/19 signaling pathway, which transmits signals to the liver, thereby affecting the hepatic FXR-SHP signaling pathway. This results in improved bile acid metabolism, ultimately reducing hepatic injury and ileal inflammation to exert hypolipidemic effects.