Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model

• Published in: PloS one 2022-02, Vol.17 (2), p.e0261310-e0261310
• Main Authors: Morishita, Asahiro, Tadokoro, Tomoko, Fujihara, Shintaro, Iwama, Hisakazu, Oura, Kyoko, Fujita, Koji, Tani, Joji, Takuma, Kei, Nakahara, Mai, Shi, Tingting, Haba, Reiji, Okano, Keiichi, Nishiyama, Akira, Ono, Masafumi, Himoto, Takashi, Masaki, Tsutomu
• Format: Article
• Language: English
• Subjects: Alanine; Alanine transaminase; Alanine Transaminase - genetics; Alanine Transaminase - metabolism; Analysis; Animal models; Animals; Antioxidants; Aspartate Aminotransferases - genetics; Aspartate Aminotransferases - metabolism; Aspartate transaminase; Beta cells; Biology and life sciences; Blood Glucose - metabolism; Complications and side effects; Depletion; Development and progression; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes therapy; Disease Models, Animal; Drugs; Fasting; Fatty liver; Fibrosis; Gastroenterology; Gene Expression Profiling; Gene Expression Regulation; Glucose; Glucosides - pharmacology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Hypoglycemic Agents - pharmacology; Inflammation; Insulin; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Male; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - classification; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mitochondria; Neurology; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oxidative stress; Patient outcomes; Physical Sciences; Proximal tubules; Reabsorption; Research and Analysis Methods; Signal Transduction; Sodium; Sodium-glucose cotransporter; Steatosis; Streptozocin - administration & dosage; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Thiophenes - pharmacology; Transaminase; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0261310

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.