title: Non-alcoholic steatohepatitis-associated hepatic fibrosis and hepatocellular carcinoma in a combined mouse model of genetic modification and dietary challenge.
abstract: OBJECTIVE
  Experimental models of non-alcoholic steatohepatitis (NASH) are still required for understanding the pathophysiology of this disease. This study aimed to examine whether disease progression is accelerated by combining dyslipidemic genetic modification and dietary challenges and develop NASH-associated hepatic fibrosis, cirrhosis, and carcinoma in a short period.
  
  
  METHODS
  Low-density lipoprotein receptor knockout mice were fed a modified choline-deficient amino acid-defined diet, including 1 w/w% cholesterol and 41 kcal% fat, and was comprehensively profiled over 1 year.
  
  
  RESULTS
  Microvesicular and macrovesicular steatosis in the liver was observed from the first week after starting the modified choline-deficient amino acid-defined diet. Macrovesicular steatosis was exacerbated with time and was observed in almost all hepatocytes at week 8, but slightly decreased at week 16. Infiltration of macrophages and neutrophils, and upregulation of hepatic inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β were also observed from week 1. Plasma hepatic transaminase activities were increased at week 1, reached a peak at week 4, and gradually decreased thereafter. In parallel with increases in hepatic gene expression of collagen-I, the hepatic fibrosis area expanded after week 4 and massively spread all over the liver by week 8. Hepatocellular hyperplasia was observed from week 24. Hepatocellular adenoma and carcinoma were observed from week 31 and 39, respectively.
  
  
  CONCLUSIONS
  These results suggest that, in a rodent NASH model with the combination of genetic modification and dietary challenges, hepatic steatosis, inflammatory cell infiltration and hepatic injury, hepatic fibrosis, hepatocellular hyperplasia, adenoma, and carcinoma can be developed in a relatively short period.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Amano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasuno
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Harada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Shuntarou
authors.initials: S
authors.lastname: Tsuchiya
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Isono
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
keywords: CDAA diet; LDL receptor knockout mouse; adenoma; carcinoma; hepatic fibrosis; non-alcoholic steatohepatitis