Role of the cascade PPARγ–adiponectin–AMPK in the control of hepatic fibrogenesis and steatohepatitis
(2009)
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- Authors
- Supervisors
- Leclercq, Isabelle
- Abstract
- (en) Several studies have demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) agonists, such as pioglitazone (PGZ), improve metabolic parameters and histology of nonalcoholic steatohepatitis (NASH) development in humans and mice, and have beneficial effects on liver fibrosis in rats. NASH, characterized by steatosis, hepatocellular damage, inflammation and variable fibrosis, is recognised as the hepatic complication of the metabolic syndrome. Obesity, one of the risk factors for NASH development, is characterized by low serum adiponectin levels. This adipocytokine, of which gene expression is regulated by PPARγ, demonstrates anti-steatotic and anti-fibrotic properties in mice. Intracellular activity of adiponectin is mediated through its specific receptors which activate AMP-activated protein kinase (AMPK) and PPARalpha. Once activated, AMPK switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis). Activation of PPARalpha increases fatty acid oxidation and reduces inflammatory reaction. The aim of the present work is to analyse the activation of the axis PGZ-adiponectin-AMPK and/or PPARalpha as a way to control NASH and hepatic fibrosis development. We first evaluated the effect of PGZ on hepatic fibrosis in mice. We observed that, by contrast with results in rats, PGZ did not prevent hepatic fibrosis development in vivo in mice. These results were confirmed by in vitro studies on the key effector cells of fibrogenesis, the hepatic stellate cells (HSCs). We then assessed the impact of AMPK on hepatic fibrosis in vivo and on HSC trans-differentiation/activation phenomenon in vitro. We found that AMPK played a role in the control of HSC trans-differentiation in vitro but was not implicated in the wound-healing fibrosis in vivo in mice. Finally, we tested the hypothesis that the beneficial effect of PGZ on steatohepatitis results from the adiponectin-dependent stimulation of AMPK and/or PPARalpha. We found that this preventive effect was clearly dependent of adiponectin but did not involve AMPK or PPARalpha activation. We have also identified SREBP-1c, implicated in the regulation of de novo lipogenesis, as a potential therapeutic target for the control of the development of NASH. The present thesis provides a better understanding of the axis PPARγ–adiponectin–AMPK in the control of NASH and hepatic fibrosis development in mouse.
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Citations
Da Silva Morais, A. (2009). Role of the cascade PPARγ–adiponectin–AMPK in the control of hepatic fibrogenesis and steatohepatitis. https://hdl.handle.net/2078.5/130874