Sodium-Glucose Cotransporter-2 Inhibition Exacerbates Hepatic Encephalopathy in Biliary Cirrhotic Rats.

Abstract

In liver cirrhosis, hepatic inflammation and abundant portal-systemic collaterals are indicated for the development of hepatic encephalopathy. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a type of anti-diabetic agent which exert pleiotropic and anti-inflammatory effects. Diabetes and chronic liver disease often coexist, but the influence of SGLT-2 inhibition on liver cirrhosis and hepatic encephalopathy remains unknown. This study investigated the effect of SGLT-2 inhibition on cirrhotic rats. Biliary cirrhosis was induced in Sprague-Dawley rats via common bile duct ligation. A total of two weeks of treatment with the SGLT-2 inhibitor, empagliflozin 30 mg/kg/d, was applied. The motor activities, hemodynamics, biochemistry parameters, plasma levels of vascular endothelial growth factor (VEGF), and the severity of portal-systemic collateral shunts were measured. The hepatic histopathology and protein expressions were examined. We found that empagliflozin treatment did not affect hemodynamics, liver biochemistry, or blood glucose levels in cirrhotic rats. Empagliflozin did not affect hepatic inflammation and fibrosis. The protein expression of factors related to liver injury were not influenced by empagliflozin. However, empagliflozin decreased motor activities in cirrhotic rats and increased portal-systemic collateral shunts and VEGF plasma levels. In summary, SGLT-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic inflammation in cirrhotic rats. In contrast, it exacerbated hepatic encephalopathy, which was evidenced by a decrease in motor activity. A possible mechanism could be an increase of portal-systemic shunts related to VEGF upregulation. Therefore, empagliflozin use should be cautious in cirrhotic patients regarding the development of hepatic encephalopathy. SIGNIFICANCE STATEMENT: Sodium-glucose cotransporter-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic inflammation in cirrhotic rats. In contrast, it exacerbated hepatic encephalopathy through increased portal-systemic shunts related to VEGF up-regulation.

• Authors: Shao-Jung Hsu, Hui-Chun Huang, Chon Kit Pun, Ching-Chih Chang, Chiao-Lin Chuang, Yi-Hsiang Huang, Ming-Chih Hou, Fa-Yauh Lee
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 383 Issue 1 Pg. 25-31 (10 2022) ISSN: 1521-0103 [Electronic] United States
• PMID: 35926870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Vascular Endothelial Growth Factor A
• Sodium-Glucose Transporter 2 Inhibitors

Topics

• Animals
• Rats
• Hepatic Encephalopathy (drug therapy, complications)
• Hypertension, Portal (complications, drug therapy, metabolism)
• Liver Cirrhosis (complications, drug therapy, metabolism)
• Rats, Sprague-Dawley
• Vascular Endothelial Growth Factor A (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology)