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[Effect of pure total flavonoids from citrus on hepatic SIRT1/PGC-1alpha pathway in mice with NASH]
Objective:
To observe the effect of pure total flavonoids from Citrus (PTFC) on the hepatic fatty degeneration, inflammation, oxidative stress and SIRT1/PGC-1alpha expressions in mice with non-alcohol steatohepatitis (NASH), and discuss the action mechanism of PTFC on NASH.
Method:
Mice were given high-fat diet for 16 weeks to induce the NASH model. Since the seventh week after the model establishment, the mice were intervened with 100, 50 and 25 mg x kg(-1) x d(-1) PTFC for 10 weeks. The pathologic changes in hepatic tissues were observed with HE staining. The contents of TG, CHOL in hepatic tissue, as well as the levels of AST, ALT in serum were detected by using the biochemical process. The expression of SIRT1, PGC-1alpha and MnSOD mRNA in hepatic tissues were detected with Real-time PCR assay. SIRT1, PGC-1alpha protein and 8-OHdG expressions were determined with the immunohistochemical method. The SOD level in hepatic tissues was tested by the xanthine oxidase method. The MDA content in hepatic tissues was examined by the thiobarbituric acid method.
Result:
The contents of TG, CHOL, NAFLD activity scores and ALT level in serum in hepatic tissues of mice in the model induced by fat-rich diet were obviously higher than that of the normal group (P < 0.010. The SIRT1, PGC-1alpha, MnSOD mRNA and protein expression in hepatic tissues were significantly lower than that of the normal group (P < 0.01). The expression of 8-OHdG and the content of MDA in hepatic tissues were obviously higher than that of the normal group (P < 0.01). After the intervention with different doses of PTFC, the NAFLD activity scores, the content of TG and the level of AST in serum were notably lower than that of the normal group (P < 0.01, P < 0.05); whereas the SIRT1, PGC-1alpha, MnSOD mRNA and protein expression were obviously higher than that of the normal group (P < 0.01, P < 0.05), with the significant decrease in the expression of 8-OHdG and the content of MDA (P < 0.01).
Conclusion:
Oxidative stress/lipid peroxidation enhancement in in NASH mice induced by high-fat diet may be related to the changes in SIRT1/PGC-1alpha signal transduction pathway. PTFC could enhance the anti-oxidant capacity in liver, relieve the damage of reactive oxygen during the fatty acid metabolic process, and prevent NASH from the occurrence and development by regulating the SIRT1/PGC-1alpha signal pathway.
Insights
Pure total flavonoids from Citrus (PTFC) can prevent non-alcoholic steatohepatitis (NASH) by enhancing antioxidant capacity and regulating the SIRT1/PGC-1alpha pathway. This study shows PTFC improves liver health in NASH mice.
Area of Science:
- Hepatology
- Pharmacology
- Biochemistry
Background:
- Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized by inflammation, oxidative stress, and fatty degeneration.
- The SIRT1/PGC-1alpha signaling pathway plays a crucial role in regulating hepatic metabolism and cellular stress responses.
- Pure total flavonoids from Citrus (PTFC) are potential therapeutic agents with antioxidant properties.
Purpose of the Study:
- To investigate the effects of PTFC on hepatic fatty degeneration, inflammation, and oxidative stress in a mouse model of NASH.
- To elucidate the mechanism of PTFC action on NASH, focusing on the modulation of the SIRT1/PGC-1alpha pathway.
Main Methods:
- NASH was induced in mice using a high-fat diet.
- Mice were treated with varying doses of PTFC (25, 50, 100 mg/kg/day) for 10 weeks.
- Hepatic histopathology, lipid profiles (TG, CHOL), liver enzymes (AST, ALT), oxidative stress markers (SOD, MDA, 8-OHdG), and SIRT1/PGC-1alpha expression (mRNA and protein) were assessed.
Main Results:
- High-fat diet significantly increased hepatic lipid accumulation, inflammation, and oxidative stress markers while downregulating SIRT1/PGC-1alpha expression in NASH mice.
- PTFC treatment dose-dependently ameliorated hepatic steatosis, reduced liver enzyme levels, and decreased oxidative stress.
- PTFC intervention significantly upregulated the expression of SIRT1, PGC-1alpha, and MnSOD, and reduced 8-OHdG and MDA levels.
Conclusions:
- The pathogenesis of NASH in this model involves oxidative stress and lipid peroxidation, potentially linked to dysregulation of the SIRT1/PGC-1alpha pathway.
- PTFC demonstrates significant hepatoprotective effects in NASH mice by enhancing antioxidant capacity and mitigating oxidative damage.
- PTFC exerts its therapeutic effects by modulating the SIRT1/PGC-1alpha signaling pathway, suggesting its potential as a novel treatment for NASH.
