Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

Nov 7, 2012Clinical and experimental pharmacology & physiology

Thiazolidinediones may improve liver scarring in rats with fatty liver disease by activating energy-regulating pathways

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Abstract

Pioglitazone significantly reduced hepatic steatosis and fibrosis in rats with non-alcoholic steatohepatitis (NASH).

Rats with a high-fat diet showed significantly higher levels of hepatic steatosis and fibrosis compared to normal controls.
Serum concentrations of aminotransaminase, triglycerides, free fatty acids, glucose, insulin, and TGF-β1 were elevated in high-fat diet-induced NASH rats.
Serum adiponectin levels and hepatic expression of adiponectin mRNA and AMPK protein were significantly lower in NASH rats compared to controls.
Pioglitazone treatment led to reductions in serum aminotransaminase, triglycerides, free fatty acids, glucose, insulin, and TGF-β1 levels.
The treatment also increased serum adiponectin concentrations and hepatic expression of adiponectin mRNA and AMPK protein.

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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.

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Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

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