Abstract
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.
Highlights
Non-alcoholic steatohepatitis (NASH) is the advanced stage of non-alcoholic fatty liver disease (NAFLD) and is one of the most common chronic liver diseases worldwide with a global prevalence of approximately one-fourth of the adult population [1]
Since the intestinal and hepatic axes are known to play an important role in NAFLD/NASH, we examined the expression of SGLT1 and sodium glucose cotransporter 2 (SGLT2) in the intestinal cells of STAM mice
Our present study demonstrated that ipragliflozin improved NASH development and identified a new mitochondrial pathway and a key miRNA that were regulated by ipragliflozin in a NASH mouse model
Summary
Non-alcoholic steatohepatitis (NASH) is the advanced stage of non-alcoholic fatty liver disease (NAFLD) and is one of the most common chronic liver diseases worldwide with a global prevalence of approximately one-fourth of the adult population [1]. NAFLD comprises various pathological conditions ranging from simple steatosis to NASH, cirrhosis, and HCC [6]. Various drugs such as vitamin E [7, 8], peroxisome proliferator-activated receptor gamma agonists [9, 10], ursodeoxycholic acid [11, 12], antioxidants [11], insulin-sensitizing agents, glucose-lowering drugs [13–18], and lipid-lowering drugs [19–21] have been used for the treatment of NASH. Despite numerous clinical trials and tremendous efforts, there is still no definitive therapy for NASH Lifestyle alterations, such as exercise and diet control, are currently one of the most effective therapies for NASH [22]. Such changes bring about better outcomes, they are hard to achieve and maintain for the majority of NASH patients, resulting in poor condition requiring pharmacological therapy
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