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TSG attenuated NAFLD and facilitated weight loss in HFD-fed mice via activating the RUNX1/FGF21 signaling axis
Zhen-Lin Huang1, Shao-Bo Zhang1, Shang-Fu Xu2
1The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by steatosis in hepatocytes and is now becoming the major cause of liver-related mortality. Fibroblast growth factor 21 (FGF21) is an endocrine hormone mainly secreted by the liver, which can bind to its receptor (FGFR) and co-receptor beta klotho (KLB) to form a receptor complex, exerting its lipid-lowering function. 2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), a natural compound isolated from Polygonum multiflorum Thunb, has shown excellent activity in lowering lipid content and efficacy in improving NAFLD. In this study we investigated whether FGF21 was implicated in the therapeutic effect of TSG in NAFLD mice. NAFLD was induced in mice by feeding with a high-fat diet (HFD) for 12 weeks, and treated with TSG (20, 40 mg·kg-1·d-1, i.g.) during the last 4 weeks. We showed that TSG treatment significantly alleviated NAFLD in HFD-fed mice evidenced by reduced hepatic triglyceride (TG) and non-esterified fatty acids (NEFA), diminished lipid droplets and decreased NAFLD activity score (NAS) in liver tissues. We demonstrated that TSG treatment significantly increased the mRNA and protein levels of FGF21 in vitro and in vivo, and reduced lipid accumulation in both the liver and adipose tissues. Transcriptomics analysis revealed that TSG treatment significantly increased the nuclear translocation of a transcription factor RUNX1. Knockdown of Runx1 in HFD-fed mice eliminated the efficacy of TSG in alleviating NAFLD, reducing hepatic lipid accumulation and regulating FGF21 signaling pathway in liver and adipose tissues. In conclusion, TSG alleviates NAFLD by enhancing the FGF21-mediated lipid metabolism in a RUNX1-dependent manner.
Insights
The natural compound TSG alleviates non-alcoholic fatty liver disease (NAFLD) by boosting Fibroblast Growth Factor 21 (FGF21) levels. This effect is dependent on the transcription factor RUNX1, which is crucial for TSG
Area of Science:
- Hepatology
- Endocrinology
- Molecular Biology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a growing cause of liver mortality.
- Fibroblast Growth Factor 21 (FGF21) is a key hormone regulating lipid metabolism.
- 2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) shows potential in improving NAFLD.
Purpose of the Study:
- To investigate the role of FGF21 in the therapeutic effects of TSG on NAFLD.
- To elucidate the molecular mechanisms underlying TSG's efficacy in NAFLD treatment.
Main Methods:
- NAFLD was induced in mice using a high-fat diet (HFD).
- Mice were treated with TSG, and liver tissues were analyzed for lipid content and NAFLD activity score.
- Gene expression and protein levels of FGF21 were assessed.
- Transcriptomics analysis identified RUNX1 as a key mediator.
Main Results:
- TSG treatment significantly reduced hepatic lipids, lipid droplets, and NAFLD activity score in HFD-fed mice.
- TSG increased FGF21 expression and reduced lipid accumulation in liver and adipose tissues.
- TSG promoted RUNX1 nuclear translocation, and RUNX1 knockdown abolished TSG's therapeutic effects.
Conclusions:
- TSG alleviates NAFLD by enhancing FGF21-mediated lipid metabolism.
- The therapeutic mechanism of TSG in NAFLD is dependent on the transcription factor RUNX1.
