Given the synergistic effect of hypoxia and insulin resistance in liver fibrosis, previous study showed that hypoxia leads to a decrease in PPARγ expression, followed by inhibition of IR transcription, resulting in the blockade of IGF-1 and subsequent signals. When TZD restores PPARγ, IR activation occurs directly and indirectly, initiating IGF-1/PI3K signaling . However, we found that the hypoxic environment induced the PI3K signals, leading to the decrease of PPARγ expression, indicating that there is a complex negative feedback mechanism in this process.