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Moronic acid alleviates non-alcoholic fatty liver disease and fibrosis through PPARs-mediated lipidomic reprogramming
Jinlu Han1, Jiong Chen1, Hong Hu1
1Department of Gastroenterology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China.
Background:
Non-alcoholic fatty liver disease (NAFLD) and its fibrotic progression represent major global health concerns with limited pharmacological interventions. Moronic acid (MA), a natural pentacyclic triterpenoid, has demonstrated anti-inflammatory and metabolic activity, but its role in NAFLD and fibrosis remains unclear.
Purpose:
This study aimed to elucidate the therapeutic potential and mechanism of MA in ameliorating NAFLD and liver fibrosis.
Methods:
The therapeutic effects of MA were evaluated in C57BL/6 J mouse models of NAFLD and fibrosis. An integrated multi-omics approach, combining network pharmacology, proteomics, and lipidomics, was used to investigate the underlying mechanism. Direct binding to the identified target, peroxisome proliferator-activated receptors (PPARs), and cellular engagement were confirmed by microscale thermophoresis (MST) and Cellular Thermal Shift Assay (CETSA). The dependency on this pathway was genetically validated using siRNA-mediated gene silencing and further confirmed in a 3D human liver organoid model.
Results:
MA alleviated hepatic steatosis, fibrosis, and metabolic dysregulation in both models. MA activated PPARα/β/γ, as evidenced by molecular docking, dynamics simulations, and increased hepatic expression. In hepatocytes and hepatic stellate cells, MA reduced lipid accumulation and fibrogenesis, effects reversed by PPAR inhibition. Lipidomic profiling showed that MA upregulated glycerophospholipids and sphingolipids and downregulated glycerolipids, consistent with PPAR-driven lipid remodeling.
Conclusion:
MA exerts therapeutic effects against NAFLD and fibrosis through PPAR activation and lipidomic reprogramming. These findings support the potential of MA as a novel phytotherapeutic agent for metabolic liver disease.
Insights
Moronic acid (MA) effectively treats non-alcoholic fatty liver disease (NAFLD) and fibrosis by activating PPARs and reprogramming lipids. This natural compound shows promise as a phytotherapeutic agent for metabolic liver conditions.
Area of Science:
- Hepatology
- Pharmacology
- Metabolomics
Background:
- Non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are significant global health issues.
- Current pharmacological interventions for NAFLD and fibrosis are limited.
- Moronic acid (MA), a natural pentacyclic triterpenoid, possesses anti-inflammatory and metabolic activities, but its therapeutic role in NAFLD and fibrosis is not well-defined.
Purpose of the Study:
- To investigate the therapeutic potential of Moronic acid (MA) in ameliorating NAFLD and liver fibrosis.
- To elucidate the underlying molecular mechanisms of MA's action in metabolic liver disease.
Main Methods:
- MA's efficacy was assessed in mouse models of NAFLD and liver fibrosis.
- An integrated multi-omics approach (network pharmacology, proteomics, lipidomics) was employed to uncover the mechanism of action.
- Direct target engagement with peroxisome proliferator-activated receptors (PPARs) was confirmed using biophysical assays (MST, CETSA) and genetic validation.
Main Results:
- MA treatment significantly alleviated hepatic steatosis, fibrosis, and metabolic dysregulation in preclinical models.
- MA was found to activate PPARα/β/γ, leading to reduced lipid accumulation and fibrogenesis in liver cells.
- Lipidomic analysis revealed MA-induced alterations in glycerophospholipid and sphingolipid metabolism, consistent with PPAR pathway activation.
Conclusions:
- Moronic acid (MA) demonstrates significant therapeutic effects against NAFLD and liver fibrosis.
- MA acts by activating PPARs and reprogramming lipid metabolism.
- These findings highlight MA's potential as a novel phytotherapeutic agent for managing metabolic liver diseases.
