title: Pharmacological evaluation of pioglitazone and candesartan cilexetil in a novel mouse model of non-alcoholic steatohepatitis, modified choline-deficient, amino acid-defined diet fed low-density lipoprotein receptor knockout mice.
abstract: OBJECTIVE
  Low-density lipoprotein receptor knockout (LDLR-KO) mice fed a modified choline-deficient and amino acid-defined (mCDAA) diet show non-alcoholic steatohepatitis (NASH)-like pathophysiology. In order to pharmacologically benchmark this model, effects of pioglitazone (a thiazolidinedione) and candesartan cilexetil (an angiotensin II type 1 receptor blocker) on steatosis and liver fibrosis were examined.
  
  
  METHODS
  Pioglitazone (10 mg/kg) and candesartan cilexetil (3 mg/kg) were given orally once daily to LDLR-KO mice under mCDAA diet for 7 weeks. Blood biochemistry and hepatic histology were assessed, and hepatic gene expression levels and triglyceride content were measured.
  
  
  RESULTS
  Pioglitazone suppressed hepatic COL1A1 gene expression by 43% and attenuated hepatic fibrosis areas by 49%. Pioglitazone also decreased plasma alanine aminotransferase levels, liver weight, hepatic triglyceride content, and hepatic expression of other fibrosis-related genes such as TGFB1, SPP1, TIMP1, and IL6. Candesartan cilexetil suppressed hepatic COL1A1 gene expression by 33%, whereas the other end-points including hepatic fibrosis areas were not affected.
  
  
  CONCLUSIONS
  Pioglitazone showed anti-fibrotic effects accompanied by improving hepatic transaminase activity and hepatic lipid accumulation, but the effect of candesartan cilexetil was only limited, unlike previous reports for angiotensin II type 1 receptor blockers. As the pharmacological effects of pioglitazone in the current animal model are similar to those reported in patients with NASH, this model may represent some aspects of the pathophysiology of NASH. Further profiling using other agents or mechanisms that have been tested in the clinic will better clarify the utility of the animal model.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Shuntarou
authors.initials: S
authors.lastname: Tsuchiya
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Amano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Isono
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Imai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Asada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Shigemitsu
authors.initials: S
authors.lastname: Imai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Harada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yasuhara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
keywords: LDL receptor knockout mouse; candesartan cilexetil; hepatic fibrosis; non-alcoholic steatohepatitis; pioglitazone