PPAR antagonizes hypoxia-induced activation of hepatic stellate cell through cross mediating PI3K/AKT and cGMP/PKG signaling

Abstract

Background and Aims. Accumulating evidence reveals that PPAR 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 PPAR 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 PPAR 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 PPAR and two fibrosis markers, -SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPAR, -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 PPAR on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPAR. Conclusion. sGC/cGMP/PKG and PI3K/AKT signals act on PPAR synergistically to attenuate hypoxia-induced HSC activation.