title: Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats.
abstract: Ipragliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that increases urinary glucose excretion by inhibiting renal glucose reabsorption and thereby causes a subsequent antihyperglycemic effect. As nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is closely linked to metabolic diseases such as obesity and diabetes, we investigated the effect of ipragliflozin on NAFLD in rats fed a choline-deficient l-amino acid-defined (CDAA) diet. Five weeks after starting the CDAA diet, rats exhibited hepatic triglyceride (TG) accumulation, fibrosis, and mild inflammation. Repeated oral administration of ipragliflozin (3mg/g, once daily for 5 weeks) prevented both hepatic TG accumulation (188 vs.290 mg/g tissue vehicle-treated group; P<0.001) and large lipid droplet formation. Further, ipragliflozin exerted a prophylactic effect on liver fibrosis, as indicated by a marked decrease in hydroxyproline content and fibrosis score. Pioglitazone, which is known to be effective on hepatic fibrosis in CDAA diet-fed rats as well as NASH patients with type 2 diabetes mellitus (T2DM), also exerted a mild prophylactic effect on fibrosis, but not on hepatic TG accumulation or inflammation. In conclusion, ipragliflozin prevented hepatic TG accumulation and fibrosis in CDAA-diet rats. These findings suggest the therapeutic potential of ipragliflozin for patients with NAFLD.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. Electronic address: yuka.hayashizaki@astellas.com.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hayashizaki-Someya
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takasu
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Mitori
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Koide
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002796:Choline Deficiency / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005526:Food, Formulated / Q000009:adverse effects*; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D006909:Hydroxyproline / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D000077205:Pioglitazone; D051381:Rats; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000596:Amino Acids; D005960:Glucosides; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones; D013876:Thiophenes; D014280:Triglycerides; C572941:ipragliflozin; D006909:Hydroxyproline; D000077205:Pioglitazone
keywords: Choline-deficient and amino acid-defined diet; Ipragliflozin l-proline (PubChem CID: 57339444); Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Pioglitazone (PubChem CID: 4829); SGLT2 inhibitor