4-Hydroxynonenal signalling to apoptosis in isolated rat hepatocytes: The role of PKC-δ

4-Hydroxynonenal, a significant aldehyde end product of membrane lipid peroxidation with numerous biochemical activities, has consistently been detected in various human diseases. Concentrations actually detectable in vivo (0.1–5 μM) have been shown to up-regulate different genes and modulate various enzyme activities. In connection with the latter aspect, we show here that, in isolated rat hepatocytes, 1 μM 4-hydroxynonenal selectively activates protein kinase C-δ, involved in apoptosis of many cell types; it also induces very early activation of Jun N-terminal kinase, in parallel increasing activator protein-1 DNA-binding activity in a time-dependent manner and triggering apoptosis after only 120 min treatment. These phenomena are likely protein kinase C-δ-dependent, being significantly reduced or annulled by cell co-treatment with rottlerin, a selective inhibitor of protein kinase C-δ. We suggest that 4-hydroxynonenal may induce apoptosis through activation of protein kinase C-δ and of Jun N-terminal kinase, and consequent up-regulation of activator protein-1 DNA binding.