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Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD
Zehong Yang1, Yuanyuan Yu1, Nannan Sun2
1Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
Background:
Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD.
Methods:
Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific sirtuin 6 (SIRT6, 50721) deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo.
Results:
We identified ginsenosides Rc as a novel SIRT6 activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates peroxisome proliferator activated receptor alpha (PPAR-α, 19013)-mediated fatty acid oxidation in vivo and in vitro. Hepatic specific SIRT6 deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD.
Conclusion:
Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving PPAR-α-mediated fatty acid oxidation and antioxidant capacity in a SIRT6 dependent manner, and providing a promising strategy for NAFLD.
Insights
Ginsenosides Rc combats non-alcohol fatty liver disease (NAFLD) by activating SIRT6, enhancing fatty acid oxidation, and reducing oxidative stress in mice. This offers a promising therapeutic strategy for NAFLD.
Area of Science:
- Metabolic Disorders
- Hepatology
- Pharmacology
Background:
- Hepatic lipid disorder contributes to non-alcohol fatty liver disease (NAFLD) by disrupting mitochondrial function and redox balance.
- Current therapeutic strategies for NAFLD remain insufficient.
- Ginsenosides Rc's role in lipid metabolism and NAFLD is unexplored.
Purpose of the Study:
- To investigate the protective function and underlying mechanism of ginsenosides Rc against high-fat diet (HFD)-induced NAFLD.
- To determine if ginsenosides Rc can modulate lipid metabolism and related signaling pathways.
Main Methods:
- Primary hepatocytes and HFD-induced mouse models were used to assess ginsenosides Rc effects on lipid metabolism.
- RNA sequencing and molecular docking identified potential targets.
- In vivo studies involved wild-type and liver-specific SIRT6-deficient mice treated with ginsenosides Rc.
Main Results:
- Ginsenosides Rc activates sirtuin 6 (SIRT6) expression and deacetylase activity, protecting against lipid deposition in hepatocytes.
- Ginsenosides Rc treatment ameliorated HFD-induced metabolic dysfunction, including glucose intolerance, insulin resistance, oxidative stress, and inflammation.
- The protective effects were dependent on SIRT6 and involved enhanced peroxisome proliferator-activated receptor alpha (PPAR-α)-mediated fatty acid oxidation.
Conclusions:
- Ginsenosides Rc demonstrates hepatoprotective effects against HFD-induced steatosis via SIRT6 activation.
- It enhances PPAR-α-mediated fatty acid oxidation and antioxidant capacity, offering a potential therapeutic approach for NAFLD.
