IDDF2024-ABS-0318 Ligusticum cycloprolactam (LIGc), a novel FXR agonist: target activation of FXR ameliorate metabolic associated fatty liver disease

Background

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as the predominant chronic liver disease globally. The farnesoid X receptor (FXR) is recognized as a crucial therapeutic target in MAFLD management. However, traditional FXR agonists, such as obeticholic acid, present significant safety risks that limit their clinical utility. Ligusticum cycloprolactam (LIGc), a derivative of ligusticum extracted from traditional Chinese herbs Ligusticum chuanxiong Hort, has shown promising outcomes in obesity and diabetes treatment. Despite these advances, the specific effects and underlying mechanisms of LIGc in MAFLD treatment remain poorly understood.

Methods

The therapeutic effect of LIGc was detected by a high-fat diet (HFD) or HFD combined with streptozotocin (STZ)-induced MAFLD mice model. RNA sequencing analysis was utilized to identify significantly differentially expressed genes and pathways in the livers of mice. 16S rRNA sequence analysis was performed to evaluate the impact of LIGc on intestinal microbiota composition. Molecular docking techniques constructed the three-dimensional structure of proteins to explore interactions and binding sites.

Results

We found that LIGc improved hepatic glucolipid metabolic disorder, insulin resistance, inflammation and fibrosis in MAFLD mice (Figure 1. LIGc improves meta-inflammation and fibrosis in the livers of HFD-induced MAFLD mice; Figure 2. LIGc ameliorates meta-inflammation and fibrosis in the livers in mice with type 2 diabetes mellitus associated MAFLD). Subsequently, RNA-seq analysis found that LIGc significantly inhibited hepatic MAPK and TGF-β signaling pathways involved in inflammation and fibrosis (Figure 3. Transcriptomic analysis revealed the key differential targets in LIGc treatment MAFLD mice). Molecular docking indicated that LIGc was able to bind to FXR directly. Furthermore, WB assay confirmed that LIGc significantly up-regulated hepatic FXR (Figure 4. LIGc upregulates hepatic FXR in MAFLD mice), but did not affect the intestinal microbiota composition and the expression of FXR in intestinal (Figure 5. LIGc does not affect the expression of intestinal FXR and the composition of the gut microbiota in MAFLD mice)

Conclusions

These findings highlight LIGc is a novel FXR agonist for the treatment of MAFLD, which demonstrates selective activation of hepatic FXR, along with significant mitigation of meta-inflammation and fibrosis.