Figure 6.

Proposed scheme for PAHSA synthesis. DNL from glucose to palmitate is controlled by ChREBP. Membrane phospholipids (PhL) are oxidized to phospholipid hydroperoxide (PhL-OOH), which is further converted to a phospholipid with the hydroxy fatty acid (PhL-OH) via GSH-dependent peroxidases. The hydroxy fatty acid (HSA) is liberated from the PhL-OH and subsequently coupled to acyl-CoA coming from the DNL pathway (PA), yielding a PAHSA, which can be later degraded by specific hydrolases. While DNL from glucose is an essential prerequisite for PAHSA synthesis, Nrf2 overexpression limits the DNL pathway. Therefore, it seems plausible that fine-tuning of enzymatic and nonenzymatic cellular antioxidant defenses and coordination with the DNL pathway is needed for PAHSA synthesis and that substrate specificity of peroxidases/phospholipases might play a role in the synthesis of individual regioisomers.