title: Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice.
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.
authors.affiliation: Discovery Research R&D, Kissei Pharmaceutical Co. Ltd., Nagano 399-8304, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nakano
authors.affiliation: Discovery Research R&D, Kissei Pharmaceutical Co. Ltd., Nagano 399-8304, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Katsuno
authors.affiliation: Research and Development Division, Kissei Pharmaceutical Co. Ltd., Nagano 399-8304, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Isaji
authors.affiliation: Toxicology Research Laboratory, Kissei Pharmaceutical Co. Ltd., Nagano 399-8305, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nagasawa
authors.affiliation: ZenBio, Research Triangle Park, NC 27709, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Buehrer
authors.affiliation: Apex Biostatistics, New Hill, NC 27562, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.affiliation: Islet Sciences, Raleigh, NC 27615, USA.
authors.forename: William O
authors.initials: WO
authors.lastname: Wilkison
authors.affiliation: BHV Pharma, RTP, NC 27709, USA.
authors.forename: Bentley
authors.initials: B
authors.lastname: Cheatham
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