Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades

This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at...

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Published in:Life sciences (1973) 2022-09, Vol.304, p.120695-120695, Article 120695
Main Authors: Hendawy, Ahmed S., El-Lakkany, Naglaa M., Mantawy, Eman M., Hammam, Olfat A., Botros, Sanaa S., El-Demerdash, Ebtehal
Format: Article
Language:English
Subjects:
Inflammation
Insulin resistance
Liver fibrosis
Nonalcoholic steatohepatitis
Type 2 diabetes
Vildagliptin
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Summary:This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at two doses (10 and 20 mg/kg) for 20 weeks. The induction of NASH was validated by abnormalities in hepatotoxicity indices, lipid profile, oxidative stress markers, and pathologically by marked fat deposition in hepatic tissues together with severe inflammatory cell infiltration. Moreover, NASH-affected rats demonstrated reduced insulin sensitivity manifested as elevated fasting blood glucose levels and disrupted homeostasis model assessment for insulin resistance. Vilda, at both doses, effectively abrogated all these pathological features of NASH. Mechanistically, these hepatoprotective properties of Vilda can be attributed to its antioxidant effects, anti-inflammatory effects (by inhibiting the TNF-α, NF-κB, JNK, and JAK/STAT pathways), and insulin-sensitizing effect (by upregulating the IRS-1/PI3K/Akt pathway). Besides, Vilda successfully counteracted NASH-associated liver fibrosis by downregulating the TGF-β1 pathway. The hepatoprotective and antifibrotic effects of Vilda were mostly dose-dependent. Collectively, this study offered a promising therapeutic avenue for Vilda as a novel strategy for counteracting the pathological progression of NASH and associated liver fibrosis. [Display omitted]
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2022.120695