title: Thiazolidinediones improve hepatic fibrosis in rats with non-alcoholic steatohepatitis by activating the adenosine monophosphate-activated protein kinase signalling pathway.
abstract: Thiazolidinediones (TZDs) markedly reduce hepatic steatosis in both rodents and humans. However, the effects and mechanisms of action of TZDs on hepatic fibrosis remain unclear. The aim of the present study was to determine the effects of TZDs 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.
authors.affiliation: Departments of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Yang
authors.forename: Huamei
authors.initials: H
authors.lastname: Zhou
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.forename: Keqiang
authors.initials: K
authors.lastname: Wan
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xiao
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D009929:Organ Size / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D017868:Cyclic AMP-Dependent Protein Kinases; D000077205:Pioglitazone
keywords: hepatic fibrosis; high‐fat diet; insulin resistance; non‐alcoholic steatohepatitis; thiazolidinedione