Eicosapentaenoic Acid (EPA) Alleviates LPS-Induced Oxidative Stress via the PPARα–NF-κB Axis

Metabolic-endotoxemia, characterized by the translocation of lipopolysaccharide (LPS) from Gram-negative bacteria into the bloodstream, is a key contributor to chronic low-grade inflammation associated with obesity and type 2 diabetes. This condition exacerbates metabolic disruptions by activating Toll-like receptor 4 (TLR4) on macrophages, leading to the release of pro-inflammatory cytokines and subsequent insulin resistance. Eicosapentaenoic acid (EPA/C20:5), an omega-3 polyunsaturated fatty acid, has demonstrated anti-inflammatory and antioxidative properties, but its precise mechanisms of action in mitigating LPS-induced stress remain unclear. This study investigates the pathways through which EPA/C20:5 alleviates LPS-induced oxidative stress and inflammation in macrophages. EPA pretreatment significantly reduced LPS-induced inflammatory responses, decreasing IL-1β and IL-6 expression and IL-1β secretion, and lowering the percentage of HLA-DR⁺ macrophages. EPA also attenuated ER stress, evidenced by reduced expression of ATF4, DDIT3, HSPA5/GRP78, BIP, and CHOP at both gene and protein levels. Oxidative stress was mitigated, as shown by decreased HIF1α expression, reduced ROS levels, and preservation of mitochondrial membrane potential. Importantly, EPA increased the expression of PPARα and FABP5 while inhibiting NF-κB activation independently of the TLR4-IRF5 pathway. The protective effects of EPA were abolished by PPARα inhibition with GW9662, indicating that EPA’s action is PPARα-dependent. This study highlights the modulatory role of EPA in alleviating LPS-induced oxidative stress and inflammation in macrophages through activation of the FABP5/PPARα/NF-κB axis, independently of TLR4-IRF5 signaling. These findings reveal a novel mechanism for EPA’s anti-inflammatory effects and suggest that targeting the FABP5/PPARα pathway may offer therapeutic potential for treating metabolic disorders associated with chronic inflammation.