A human-type nonalcoholic steatohepatitis model with advanced fibrosis in rabbits.
Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis, which can lead to life-threatening liver failure and the development of hepatocellular carcinoma. The aim of the present study was to create a rabbit model of NASH with advanced fibrosis (almost cirrhosis) by feeding the animals a diet supplemented with 0.75% cholesterol and 12% corn oil. After 9 months of feeding with this diet, the rabbits showed high total cholesterol levels in serum and liver tissues in the absence of insulin resistance. The livers became whitish and nodular. In addition, the number of rabbit macrophage antigen-positive cells and the expression of mRNAs for inflammatory cytokines showed a significant increase. Moreover, fibrotic septa composed of collagens and alpha-smooth muscle actin-positive cells were found between the central and portal veins, indicating alteration of the parenchymal architecture. There was also a marked increase of mRNAs for transforming growth factor-beta1 and collagen 1A1. Comprehensive analysis of protein and gene expression revealed an imbalance of the antioxidant system and methionine metabolism. We also found that ezetimibe attenuated steatohepatitis in this model. In conclusion, the present rabbit model of NASH features advanced fibrosis that is close to cirrhosis and may be useful for analyzing the molecular mechanisms of human NASH. Ezetimibe blunted the development of NASH in this model, suggesting its potential clinical usefulness for human steatohepatitis.
Ogawa
Tomohiro
T
Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahimachi, Abeno, Osaka 545-8585, Japan.
Fujii
Hideki
H
Yoshizato
Katsutoshi
K
Kawada
Norifumi
N
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism; D001384:Azetidines / Q000627:therapeutic use; D002791:Cholesterol, Dietary / Q000009:adverse effects / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism; D004195:Disease Models, Animal; D000069438:Ezetimibe; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011817:Rabbits
D000924:Anticholesteremic Agents; D000975:Antioxidants; D001384:Azetidines; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D000069438:Ezetimibe; D005947:Glucose