Canagliflozin Improves Liver Function in Rats by Upregulating Asparagine Synthetase.

Abstract

INTRODUCTION:

Canagliflozin (CANA) is a sodium-glucose cotransporter 2 inhibitor that was recently approved for treating diabetes. However, its effects on liver function are not well understood. The function of asparagine synthetase (ASNS) has been studied in several cancers but not in liver injury. Therefore, we investigated the connection between CANA and ASNS in alleviating damage (i.e., their hepatoprotective effect) in a rat liver injury model.

METHODS:

The rat model of liver injury was established using carbon tetrachloride treatment. Rats with liver injury were administered CANA orally for 8 weeks daily. After week 8, peripheral blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels. Liver histopathology was examined using hematoxylin and eosin staining to determine the degree of liver injury. Protein expression in the rat livers was examined using Western blotting.

RESULTS:

CANA treatment decreased serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels compared with those of the untreated group, demonstrating diminished liver injury. Mechanistically, CANA treatment activated AMP-activated protein kinase (AMPK), leading to increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4), which upregulated ASNS expression in liver-injured rats.

CONCLUSION:

CANA significantly alleviated liver injury by activating the AMPK/Nrf2/ATF4 axis and upregulating ASNS expression, indicating its potential for treating patients with type 2 diabetes mellitus with impaired liver function.

• Authors: Shiqi Wang, Yasong Ding, Ruoyao Dong, Hongyun Wang, Lingdi Yin, Shengnan Meng
• Journal: Pharmacology (Pharmacology) Vol. 106 Issue 11-12 Pg. 606-615 ( 2021) ISSN: 1423-0313 [Electronic] Switzerland
• PMID: 34515223 (Publication Type: Journal Article)
• Copyright: © 2021 S. Karger AG, Basel.

Chemical References

• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Sodium-Glucose Transporter 2 Inhibitors
• Canagliflozin
• Activating Transcription Factor 4
• Carbon Tetrachloride
• Adenylate Kinase
• Aspartate-Ammonia Ligase

Topics

• Activating Transcription Factor 4 (drug effects)
• Adenylate Kinase (drug effects)
• Animals
• Aspartate-Ammonia Ligase (pharmacology)
• Canagliflozin (pharmacology)
• Carbon Tetrachloride (pharmacology)
• Chemical and Drug Induced Liver Injury (pathology)
• Disease Models, Animal
• Liver (drug effects)
• Liver Function Tests
• NF-E2-Related Factor 2 (drug effects)
• Rats
• Rats, Sprague-Dawley
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology)