Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice

• Published in: Journal of clinical and experimental hepatology Vol. 5; no. 3; pp. 190 - 198
• Main Authors: Nakano, Shigeru, Katsuno, Kenji, Isaji, Masayuki, Nagasawa, Tatsuya, Buehrer, Benjamin, Walker, Susan, Wilkison, William O, Cheatham, Bentley
• Format: Journal Article
• Language: English
• Published: India Elsevier B.V 01.09.2015; Elsevier
• Subjects: Endocrinology & Metabolism; Gastroenterology and Hepatology; hepatic steatosis; NAFLD; NASH; obesity; Original; SGLT2; FFA; Farnesoid X receptor; FXR; NAFLD; MCP-1; Reactive oxygen species; Thiobarbituric acid-reactive substances; AAPH; ALT; High fat diet 32; hepatic steatosis; Tumor necrosis factor alpha; Diet-induced obesity; Nonalcoholic steatohepatitis; Remo; Nonalcoholic fatty liver disease; obesity; ORAC; Monocyte chemoattractant protein-1; AST; SGLT2; Remogliflozin etabonate; TBARS; DIO; NASH; Triglyceride; 2,2′-azobis-2-methyl-propanimidamide dihydrochloride; ER; aspartate aminotransferase; Free fatty acids; sodium glucose-dependent renal transporter 2; HFD32; TG; TNF-α; Trolox; ROS; Alanine aminotransferase; 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; Oxygen radical absorbance capacity; Endoplasmic reticulum; FFA, Free fatty acids; TNF-α, Tumor necrosis factor alpha; AAPH, 2,2′-azobis-2-methyl-propanimidamide dihydrochloride; SGLT2, sodium glucose-dependent renal transporter 2; FXR, Farnesoid X receptor; MCP-1, Monocyte chemoattractant protein-1; TBARS, Thiobarbituric acid-reactive substances; TG, Triglyceride; Remo, Remogliflozin etabonate; ALT, Alanine aminotransferase; NASH, Nonalcoholic steatohepatitis; NAFLD, Nonalcoholic fatty liver disease; ROS, Reactive oxygen species; ER, Endoplasmic reticulum; ORAC, Oxygen radical absorbance capacity; Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; HFD32, High fat diet 32; AST, aspartate aminotransferase; DIO, Diet-induced obesity
• ISSN: 0973-6883; 2213-3453
• DOI: 10.1016/j.jceh.2015.02.005

Background Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are serious conditions and are being diagnosed at an increased rate. The etiology of these hepatic disorders is not clear but involves insulin resistance and oxidative stress. Remogliflozin etabonate (Remo) is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), and improves insulin sensitivity in type 2 diabetics. In the current study, we examined the effects of Remo in a diet-induced obese mouse model of NAFLD. Methods After 11-weeks on High-Fat-Diet 32 (HFD32), C57BL/6J mice were obese and displayed characteristics consistent with NAFLD. Cohorts of obese animals were continued on HFD32 for an additional 4-week treatment period with or without Remo. Results Treatment with Remo for 4 weeks markedly lowered both plasma alanine aminotransferase (76%) and aspartate aminotransferase (48%), and reduced both liver weight and hepatic triglyceride content by 42% and 40%, respectively. Remo also reduced hepatic mRNA content for tumor necrosis factor (TNF)-α (69%), and monocyte chemoattractant protein (MCP)-1 (69%). The diet-induced increase in thiobarbituric acid-reactive substances, a marker of oxidative stress, was reduced following treatment with Remo, as measured in both liver homogenates (22%) and serum (37%). Finally, the oxygen radical absorbance capacity (ORAC) in three different SGLT2 inhibitors was determined: remogliflozin, canagliflozin and dapagliflozin. Only remogliflozin had any significant ORAC activity. Conclusions Remo significantly improved markers associated with NAFLD in this animal model, and may be an effective compound for the treatment of NASH and NAFLD due to its insulin-sensitizing and antioxidant properties.