Activation of autophagy through calcium‐dependent AMPK / mTOR and PKC θ pathway causes activation of rat hepatic stellate cells under hypoxic stress

The activation of hepatic stellate cells ( HSC s) is a prominent event in liver fibrogenesis. However, how HSC s are activated in the hypoxic microenvironment remains unclear. Here, we found that hypoxia increased autophagy in rat HSC s. Moreover, hypoxia induced an elevation of the intracellular calcium concentration ([Ca 2+ ] i ), which was abolished by the cytosolic Ca 2+ chelator or the phospholipase C ( PLC )‐specific inhibitor. Furthermore, hypoxia‐induced autophagy involved the calcium‐dependent activation of the 5ʹ‐adenosine monophosphate‐activated protein kinase ( AMPK )–mammalian target of rapamycin ( mTOR ) and protein kinase C‐theta ( PKC θ) pathways. In addition, hypoxia‐mediated activation of HSC s depended on autophagy. Our results suggest that autophagy induction via the calcium‐dependent AMPK – mTOR and PKC θ pathways might lead to the activation of HSC s during hypoxic stress.