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

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Abstract
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 (n‐3)), 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 C20:5 (n‐3) alleviates LPS‐induced oxidative stress and inflammation in macrophages. C20:5 (n‐3) 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. C20:5 (n‐3) 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, C20:5 (n‐3) increased the expression of PPARα and FABP5 while inhibiting NF‐κB activation independently of the TLR4‐IRF5 pathway. The protective effects of C20:5 (n‐3) was abolished by PPARα inhibition with GW9662, indicating that C20:5 (n‐3)’s action is PPARα‐dependent. This study highlights the modulatory role of C20:5 (n‐3) 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 C20:5 (n‐3)’s anti‐inflammatory effects and suggest that targeting the FABP5/PPARα pathway may offer therapeutic potential for treating metabolic disorders associated with chronic inflammation.
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Funding Information
  • Kuwait Foundation for the Advancement of Sciences (RA CB-2019-002)

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