Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice.
OBJECTIVE
Currently, no agent has been confirmed as preventing the fibrosing progression of non-alcoholic steatohepatitis (NASH). In this study, rosiglitazone was used in the clinical treatment of insulin resistance in patients with type 2 diabetes mellitus. However, its protective effect on non-alcoholic fibrosing steatohepatitis is not clear. The study aimed to elucidate the effect and the mechanism of rosiglitazone in inhibiting nutrition-related fibrosis in mice.


METHODS
C57BL6/J mice were fed a high fat, methionine-choline deficient (MCD) diet for 8 weeks to induce hepatic fibrosis, and rosiglitazone was given in the treated group. The effect of rosiglitazone was assessed by comparing the severity of hepatic fibrosis in liver sections, the activation of hepatic stellate cells (HSCs) and the expression of TGF-beta1 and connective tissue growth factor (CTGF).


RESULTS
At week 8, MCD-diet-induced fibrosing NASH models showed increased serum ALT and AST levels, severe hepatic steatosis, and infiltration of inflammation and fibrosis which, associated with down-regulated PPAR gamma mRNA and protein expression, up-regulated alpha-SMA protein expression and enhanced TGF-beta1, CTGF mRNA and protein expression. Rosiglitazone significantly lowered serum ALT and AST and it reduced MCD-induced fibrosis by repressing levels of alpha-SMA protein expression and pro-fibrosis factors TGF-beta1 and CTGF. It also restored expression of PPAR gamma.


CONCLUSIONS
The present study provides clear morphological and molecular biological evidence of the protective role of rosiglitazone in ameliorating nutritional fibrosing steatohepatitis. Rosiglitazone may ameliorate hepatic fibrosis by activating PPAR gamma, which can inhibit HSC activation and suppress TGF-beta1 and CTGF expression.
Nan
Yue-Min
YM
Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China. nanyuemin@163.com
Fu
Na
N
Wu
Wen-Juan
WJ
Liang
Bao-Li
BL
Wang
Rong-Qi
RQ
Zhao
Su-Xian
SX
Zhao
Jing-Min
JM
Yu
Jun
J
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015153:Blotting, Western; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005234:Fatty Liver / Q000517:prevention & control*; D055166:Hepatic Stellate Cells / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D055513:Connective Tissue Growth Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase