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Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway
Author(s) -
Zhang Wei,
Wu Rong,
Zhang Feng,
Xu Yizhi,
Liu Bo,
Yang Yingying,
Zhou Huamei,
Wang Lulu,
Wan Keqiang,
Xiao Xiaoqiu,
Zhang Xia
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12020
Subject(s) - medicine , endocrinology , pioglitazone , adiponectin , ampk , steatosis , steatohepatitis , fatty liver , insulin , fibrosis , hepatic fibrosis , protein kinase a , chemistry , diabetes mellitus , insulin resistance , type 2 diabetes , kinase , biochemistry , disease
Summary Thiazolidinediones ( TZD s) markedly reduce hepatic steatosis in both rodents and humans. However, the effects and mechanisms of action of TZD s on hepatic fibrosis remain unclear. The aim of the present study was to determine the effects of TZD s on histological changes in the liver and on the modulation by adiponectin via the AMP ‐activated protein kinase ( AMPK ) signalling pathway in rats with non‐alcoholic steatohepatitis ( NASH ). Forty rats were divided into normal control, high‐fat diet ( HFD ), pioglitazone control and pioglitazone intervention groups. After 24 weeks treatment with pioglitazone (10 mg/kg per day by gavage), changes in liver histology, serum aminotransaminase, triglyceride ( TG ), free fatty acid ( FFA ), glucose, insulin, adiponectin and transforming growth factor ( TGF )‐β1 concentrations and hepatic adiponectin, AMPK , α‐smooth muscle actin (α‐ SMA ) and collagen I expression were evaluated. The degree of hepatic steatosis and fibrosis was significantly higher in HFD ‐induced NASH rats compared with normal controls, as were serum concentrations of aminotransaminase, TG , FFA , glucose, insulin and TGF ‐β1 and hepatic expression of α‐ SMA and collagen I protein. Serum adiponectin concentrations and hepatic expression of adiponectin mRNA and AMPK protein were significantly lower in the HFD ‐induced NASH rats compared with the normal control. Pioglitazone significantly reduced the degree of hepatic steatosis and fibrosis, as well as serum concentrations of aminotransaminase, TG , FFA , glucose, insulin and TGF ‐β1 and hepatic expression of α‐ SMA and collagen I protein. In addition, pioglitazone significantly increased serum adiponectin concentrations and hepatic expression of adiponectin mRNA and AMPK protein. In conclusion, the TZD pioglitazone improved hepatic fibrosis in rats with NASH by upregulating adiponectin expression and activating AMPK , thus subsequently inhibiting the activation of hepatic stellate cells and the overproduction of extracellular matrix.