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Nakano S, Katsuno K, Isaji M, et al. Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice. J Clin Exp Hepatol. 2015;5(3):190-8doi: 10.1016/j.jceh.2015.02.005.
Nakano, S., Katsuno, K., Isaji, M., Nagasawa, T., Buehrer, B., Walker, S., Wilkison, W. O., & Cheatham, B. (2015). Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice. Journal of clinical and experimental hepatology, 5(3), 190-8. https://doi.org/10.1016/j.jceh.2015.02.005
Nakano, Shigeru, et al. "Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice." Journal of clinical and experimental hepatology vol. 5,3 (2015): 190-8. doi: https://doi.org/10.1016/j.jceh.2015.02.005
Nakano S, Katsuno K, Isaji M, Nagasawa T, Buehrer B, Walker S, Wilkison WO, Cheatham B. Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice. J Clin Exp Hepatol. 2015 Sep;5(3):190-8. doi: 10.1016/j.jceh.2015.02.005. Epub 2015 Apr 28. PMID: 26628836; PMCID: PMC4632078.
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J Clin Exp Hepatol. 2015 Sep;5(3):190-8. doi: 10.1016/j.jceh.2015.02.005. Epub 2015 Apr 28.

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

Journal of clinical and experimental hepatology

Shigeru Nakano, Kenji Katsuno, Masayuki Isaji, Tatsuya Nagasawa, Benjamin Buehrer, Susan Walker, William O Wilkison, Bentley Cheatham

Affiliations

  1. Discovery Research R&D, Kissei Pharmaceutical Co. Ltd., Nagano 399-8304, Japan.
  2. Research and Development Division, Kissei Pharmaceutical Co. Ltd., Nagano 399-8304, Japan.
  3. Toxicology Research Laboratory, Kissei Pharmaceutical Co. Ltd., Nagano 399-8305, Japan.
  4. ZenBio, Research Triangle Park, NC 27709, USA.
  5. Apex Biostatistics, New Hill, NC 27562, USA.
  6. Islet Sciences, Raleigh, NC 27615, USA.
  7. BHV Pharma, RTP, NC 27709, USA.

PMID: 26628836 PMCID: PMC4632078 DOI: 10.1016/j.jceh.2015.02.005

Abstract

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.

Keywords: AAPH, 2,2′-azobis-2-methyl-propanimidamide dihydrochloride; ALT, Alanine aminotransferase; AST, aspartate aminotransferase; DIO, Diet-induced obesity; ER, Endoplasmic reticulum; FFA, Free fatty acids; FXR, Farnesoid X receptor; HFD32, High fat diet 32; MCP-1, Monocyte chemoattractant protein-1; NAFLD; NAFLD, Nonalcoholic fatty liver disease; NASH; NASH, Nonalcoholic steatohepatitis; ORAC, Oxygen radical absorbance capacity; ROS, Reactive oxygen species; Remo, Remogliflozin etabonate; SGLT2; SGLT2, sodium glucose-dependent renal transporter 2; TBARS, Thiobarbituric acid-reactive substances; TG, Triglyceride; TNF-α, Tumor necrosis factor alpha; Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; hepatic steatosis; obesity

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