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.