PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3KAKT and cGMPPKG Signaling

Abstract EN

Background and Aims.

Accumulating evidence reveals that PPARγ plays a unique role in the regulation of hepatic fibrosis and hepatic stellate cells (HSCs) activation.

This study was aimed at investigating the role of PPARγ in hypoxia-induced hepatic fibrogenesis and its possible mechanism.

Methods.

Rats used for CCl4-induced hepatic fibrosis model were exposed to hypoxia for 8 hours each day.

Rats exposed to hypoxia were treated with or without the PPARγ agonist rosiglitazone.

Liver sections were stained with HE and Sirius red staining 8 weeks later.

HSCs were exposed to hypoxic environment in the presence or absence of rosiglitazone, and expression of PPARγ and two fibrosis markers, α-SMA and desmin, were measured using western blot and immunofluorescence staining.

Next, levels of PPARγ, α-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor.

Results.

Hypoxia promoted the induction and progress of hepatic fibrosis and HSCs activation.

Meanwhile, rosiglitazone significantly antagonized the effects induced by hypoxia.

Signaling by sGC/cGMP/PKG promoted the inhibitory effect of PPARγ on hypoxia-induced activation of HSCs.

Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPARγ.

Conclusion.

sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation.