title: Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka Long-Evans Tokushima fatty rats.
abstract: BACKGROUND
  It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have proved that anti-IR treatment can alleviate liver fibrosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long-Evans Tokushima Otsuka (LETO) rats.
  
  
  METHODS
  Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro.
  
  
  RESULTS
  OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs.
  
  
  CONCLUSIONS
  In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan. kitadem@naramed-u.ac.jp.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Douhara
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Asada
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005960:Glucosides / Q000008:administration & dosage / Q000627:therapeutic use*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009765:Obesity / Q000150:complications; D009929:Organ Size / Q000187:drug effects; D020334:Rats, Inbred OLETF; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D005960:Glucosides; D007004:Hypoglycemic Agents; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin
keywords: Insulin resistance; Liver fibrosis; SGLT2 inhibitor