Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD

Figure 6

Schematic representation of arachidonic acid metabolism and lipid peroxidation. Cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome p450s (CYPs) mediated enzymatic peroxidation of arachidonic acid (AA) to the respective metabolites. The 12-lipoxygenase (12-LO) and 15-lipoxygenase (15-LO) mediated conversion of AA to 12- and 15-hydroperoxyeicosatetraenoic acid (HpETE) and the downstream glutathione peroxidase- (GPx-) mediated conversion to the respective hydroxyeicosatetraenoic acids (12- and 15-HETE). Reactive oxygen species- (ROS-) induced lipid peroxidation (LPO) of 12- and 15-HpETE results in the generation of 4-hydroxynonenal (4-HNE) and 4-hydroxydodecadeinal (4-HDDE). These reactive aldehydes interact with and inactivate GPx, leading to an increased rate of 12-HpETE and 15-HpETE peroxidation (PMID: 29610056). The nonenzymatic peroxidation mediates conversion of AA to 4-HNE and MDA metabolites (PMID: 24999379).