Dapagliflozin dampens liver fibrosis induced by common bile duct ligation in rats associated with the augmentation of the hepatic Sirt1/AMPK/PGC1α/FoxO1 axis

Jun 13, 2024Toxicology and applied pharmacology

Dapagliflozin reduces liver scarring after bile duct blockage in rats by boosting a liver cell energy and repair pathway

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Abstract

Dapagliflozin (DAPA) reduced liver hydroxyproline content and improved liver histology after 14 and 28 days of treatment in male rats with bile duct ligation-induced liver fibrosis.

DAPA decreased hepatic enzyme levels and malondialdehyde levels, indicating reduced liver injury.
The treatment increased superoxide dismutase activity and catalase levels, suggesting enhanced antioxidant activity.
Serum levels of tumor necrotic factor alpha (TNF-α) decreased, while serum levels of AMP-activated protein kinase (AMPK) increased, indicating anti-inflammatory and potential metabolic benefits.
DAPA upregulated the expression of genes associated with liver health (Sirt1/PGC1α/FoxO1) and downregulated fibrosis-related genes (fibronectin-1, collagen-1).
Histological analysis showed significant improvements in liver tissue structure following DAPA administration.

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UNLABELLED: Liver fibrosis is considered an epidemic health problem due to different insults that lead to death. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is one of the newer anti-diabetic drugs used to manage type 2 diabetes mellitus (T2DM). DAPA exerted beneficial effects in many human and rat models due to its antioxidant, anti-inflammatory and antifibrotic activities.

AIM: Due to previously reported capabilities related to DAPA, we designed this study to clarify the beneficial role of DAPA in liver fibrosis triggered by common bile duct ligation (CBL) in male rats.

METHODS: For 14 or 28 days after CBL procedures, DAPA was administered to the rats orally at a dose of 10 mg/kg once daily. The effects of DAPA were evaluated by assaying liver enzymes, hepatic oxidant/antioxidant parameters, serum levels of tumor necrotic factor alpha (TNF-α), and AMP-activated protein kinase (AMPK). In addition, we measured the hepatic expression of fibrosis regulator-related genes along with evaluating liver histological changes.

KEY FINDINGS: DAPA successfully decreased hepatic enzymes and malondialdehyde levels, increased superoxide dismutase activity, elevated catalase levels, decreased serum levels of TNF-α, elevated serum levels of AMPK, decreased liver hydroxyproline content, upregulated Sirt1/PGC1α/FoxO1 liver gene expressions, down-regulated fibronectin-1 (Fn-1), collagen-1 genes in liver tissues, and improved the damaged liver tissues. Deteriorated biochemical parameters and histological liver insults associated with CBL were more pronounced after 28 days, but DAPA administration for 14 and 28 days showed significant improvement in most parameters and reflected positively in the histological structures of the liver.

SIGNIFICANCE: The significance of this study lies in the observation that DAPA mitigated CBL-induced liver fibrosis in rats, most likely due to its antioxidant, anti-inflammatory, and antifibrotic effects. These results suggest that DAPA's beneficial impact on liver fibrosis might be attributed to its interaction with the Sirt1/AMPK/PGC1α/FoxO1 pathway, indicating a potential mechanistic action for future exploration.

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Dapagliflozin dampens liver fibrosis induced by common bile duct ligation in rats associated with the augmentation of the hepatic Sirt1/AMPK/PGC1α/FoxO1 axis

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