Polydatin improves mitochondrial dynamics dysrhythmia by regulating BMAL1 to prevent and treat metabolic dysfunction-associated fatty liver disease.
Polydatin may improve mitochondrial function and reduce oxidative stress in MAFLD, but human studies are needed to confirm its therapeutic potential.
Where it sits
this study against the rest of the mots-c corpusSummary and findings
The study investigated the effects of polydatin (PD) on metabolic dysfunction-associated fatty liver disease (MAFLD) using FFA-induced HepG2 cells and HFD-induced MAFLD rats. PD was found to suppress lipid accumulation, reduce oxidative stress markers, and improve mitochondrial function. The therapeutic effects were linked to BMAL1-mediated mitochondrial dynamics and were abolished upon BMAL1 knockdown.
Abstract
<h4>Ethnopharmacological relevance</h4>Polygonum cuspidatum, a traditional Chinese medicine indicated for "blood stasis" and "damp-heat" disorders (e.g., arthralgia, jaundice, amenorrhea), has modern relevance as these conditions correlate with dyslipidemia, inflammation, and microcirculatory issues. Its main constituent, polydatin (PD), exhibits multiple bioactivities, yet its role in metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear.<h4>Aim of the study</h4>To elucidate the mechanisms by which PD alleviates MAFLD through BMAL1-mediated mitochondrial dynamics.<h4>Materials and methods</h4>FFA-induced HepG2 cells and HFD-induced MAFLD rats were used to evaluate the effects of PD on hepatic lipid accumulation, mitochondrial function, and oxidative stress immune imbalance via histological staining and biochemical assays. Additionally, molecular docking, molecular dynamics simulations, and BMAL1 knockdown experiments were conducted to identify potential upstream regulators.<h4>Results</h4>PD significantly suppressed lipid accumulation, reduced levels of ROS, MDA, NLRP3, TNF-α, and IL-1β, while enhancing SOD activity, thereby alleviating oxidative stress-immune imbalance. PD increased mitochondrial membrane potential (MMP), ATP content, and mtDNA copy number, reversing mitochondrial dysfunction. Notably, PD improved expression rhythms of BMAL1 and mitochondrial dynamics-related genes (DRP1, OPA1, MFN1, MFN2, FIS1), normalizing their amplitude and phase. Concurrently, PD activated the mitochondrial autophagy pathway by upregulating PINK1 and PARKIN expression, thereby facilitating timely clearance of impaired mitochondria. Most importantly, all the aforementioned therapeutic benefits of PD were abolished upon BMAL1 knockdown, establishing BMAL1 as an essential target for PD's action.<h4>Conclusion</h4>This is the first study to demonstrate that PD alleviates MAFLD by mediating BMAL1-regulated circadian rhythms of mitochondrial dynamics, positioning PD as a potential therapeutic candidate for MAFLD.
Background
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent condition linked to dyslipidemia and inflammation. Traditional Chinese medicine, particularly Polygonum cuspidatum, has been used for related disorders. This study explores the potential of its main constituent, polydatin (PD), to address MAFLD by targeting mitochondrial dynamics through BMAL1 regulation.
Methods
The study utilized FFA-induced HepG2 cells and HFD-induced MAFLD rats to assess PD's effects on hepatic lipid accumulation, mitochondrial function, and oxidative stress. Techniques included histological staining, biochemical assays, molecular docking, and BMAL1 knockdown experiments. The primary outcomes were changes in mitochondrial dynamics and oxidative stress markers.
Results
PD treatment resulted in significant suppression of lipid accumulation and reduction in oxidative stress markers such as ROS, MDA, NLRP3, TNF-α, and IL-1β. It enhanced mitochondrial membrane potential, ATP content, and mtDNA copy number, indicating improved mitochondrial function. PD also modulated the expression rhythms of BMAL1 and mitochondrial dynamics-related genes, with effects nullified by BMAL1 knockdown.
Interpretation
The findings suggest that PD may improve MAFLD by modulating mitochondrial dynamics via BMAL1. While the results are promising, they are limited to preclinical models, and the clinical significance remains uncertain. Further research in human subjects is necessary to validate these findings and determine clinical applicability.
Key findings
- PD significantly suppressed lipid accumulation in HepG2 cells and MAFLD rats.
- PD reduced ROS, MDA, NLRP3, TNF-α, and IL-1β levels.
- PD enhanced SOD activity and mitochondrial membrane potential.
- PD increased ATP content and mtDNA copy number.
- BMAL1 knockdown abolished PD's therapeutic benefits.
Limitations
- rodent only, no human data
- surrogate endpoints
- BMAL1 knockdown model
- no long-term follow-up